|Year : 2021 | Volume
| Issue : 3 | Page : 203-211
Interleukin-10: A double-edged sword in breast cancer
Chun-Ming Chang1, Ho Yin Pekkle Lam2, Hao-Jen Hsu3, Shinn-Jong Jiang4
1 Department of General Surgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation; Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
2 Institute of Medical Sciences; Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien, Taiwan
3 Department of Biochemistry, School of Medicine; Department of Life Sciences, College of Medicine, Tzu Chi University, Hualien, Taiwan
4 Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien, Taiwan
|Date of Submission||02-Jul-2020|
|Date of Decision||01-Aug-2020|
|Date of Acceptance||31-Aug-2020|
|Date of Web Publication||24-Feb-2021|
Department of Biochemistry, School of Medicine, Tzu Chi University, 701, Section 3, Zhongyang Road, Hualien
Department of Biochemistry, School of Medicine, Tzu Chi University, 701, Section 3, Zhongyang Road, Hualien
Source of Support: None, Conflict of Interest: None
Breast cancer (BC) is a frequently diagnosed cancer among women worldwide. Currently, BC can be divided into different subgroups according to the presence of the following hormone receptors: estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Each of these subgroups has different treatment strategies. However, the presence of new metastatic lesions and patient deterioration suggest resistance to a given treatment. Various lines of evidence had shown that cytokines are one of the important mediators of tumor growth, invasion, metastasis, and treatment resistance. Interleukin-10 (IL-10) is an immunoregulatory cytokine, and acts as a poor prognostic marker in many cancers. The anti-inflammatory IL-10 blocks certain effects of inflammatory cytokines. It also antagonizes the co-stimulatory molecules on the antigen-presenting cells. Here, we review the current knowledge on the function and molecular mechanism of IL-10, and recent findings on how IL-10 contributes to the progression of BC.
Keywords: Breast cancer, Cytokine, Interleukin-10, Tumor microenvironment
|How to cite this article:|
Chang CM, Lam HY, Hsu HJ, Jiang SJ. Interleukin-10: A double-edged sword in breast cancer. Tzu Chi Med J 2021;33:203-11
| Introduction|| |
Breast cancer (BC) is the most common cancer among women worldwide. According to the World Cancer Research Foundation and the American Cancer Institute, it accounts for 25.4% of the total number of new cancer cases in 2018 . Currently, BC can be divided into different categories based on the presence of the following three hormone receptors: estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) . BC lacking expression of all the three types of hormone receptors is classified as triple-negative BC (TNBC) , which makes up 12%–17% of all BC cases, and has a discouraging clinical outcome due to the lack of targeted therapy . In addition, TNBC is characterized by high nuclear grade, high mitotic activity, high metastasis rate, and low overall survival rate .
Tumor cells have the ability to escape immune surveillance and evade apoptosis ,. Tumor microenvironment (TME) is one of the reasons tumor can escape host immune response. The TME comprises of many immunosuppressive cells including regulatory T (Treg) cells, T helper type 2 (Th2) cells, tumor-associated macrophages (TAMs), myeloid-derived suppressor cells, and, in some case, Th17 cells ,,. Therefore, immunotherapy that modulates host immune response and restores immune surveillance may be a promising strategy for treating BC, particularly TNBC.
The relative low survival rate of BC has been suggested to be associated with lymph node (LN) metastasis. In a multivariate analysis, lymphatic invasion, but not vascular invasion, was identified as a poor prognostic factor in patients with BC ,. In addition, lymphatic vessel proliferation and LN metastasis, which are the events related with BC malignancy, were associated with dense infiltration of inflammatory cells ,, particularly tumor infiltrating lymphocytes (TILs) and TAMs ,.
More currently, the presence of TILs has been used to predict patient's response to chemotherapy in different subtypes of BC and other cancers ,,,. For example, increased TILs are associated with better prognosis in HER2-positive BC and TNBC, while it is associated with a worse prognosis in luminal-HER2-negative BC. TILs consist predominantly of T cells. CD8+ T cells and natural killer (NK) cells usually correlate with favorable outcomes as these cells aid in tumor cell destruction ,. CD4+ T cells enhance penetration of CD8+ T cells by producing Th1 cytokines and activate antigen-presenting cells (APCs) such as dendritic cells to participate in anti-tumor responses . M0 (nonactivated type) macrophages can polarize to M1 (pro-inflammatory, anti-tumor type) and M2 (anti-inflammatory type) states and produce certain cytokines. The cytokines produced by these cells can affect various stages of tumor progression, including initiation, promotion, proliferation, tumor cell transition, angiogenesis, invasion, immune surveillance escape, metastasis, and drug resistance . BC is not a cold tumor that contains only few infiltrating T cells. Instead, immune cells usually infiltrate the tumors and its TME. However, the TME is generally in an immunosuppressive state.
Various lines of evidence had shown that increased Treg cells in BC confer a more aggressive phenotype, which is characterized by decreased survival rate and increased relapse rate ,,. Tumor shrink was observed in a Treg depletion BC model, suggesting that the presence of Treg cells can promote tumor cell growth and metastasis ,,,. In an oncogene-driven BC model, transient removement of Treg cells led to the reduction of both primary and metastatic tumors . The existence of Treg cells in the TME has been found to be associated with human tumors' development and metastasis including BC ,,,. Although experiments have demonstrated that Treg cell can be used as a therapeutic target, the nature of Treg cells in human tumors remains unclear.
Treg cells have shown to be associated with many cytokines that are known to survey BC ,. Interleukin 10 (IL-10), of all, plays an important coordination role in the occurrence of BC . IL-10 is one of the anti-inflammatory cytokines, and can inhibit inflammatory responses by antagonizing the co-stimulatory molecules expressed on the APCs . Here, we review the function and molecular mechanism of IL-10, and how IL-10 contributes to the progression of BC.
| Interlukin-10|| |
The gene of IL-10 locates on chromosome 1 at q31-32  and is composed of five exons . IL-10 protein encoded by this gene consists of 160 amino acids with a molecular weight of 18 kDa and forms a dimer to exert its function . Human IL-10 shows 73% amino acid sequence similarity with murine IL-10 . IL-10 is expressed by many immune cells including macrophages, T cells, and NK cells , and is a pleiotropic cytokine that has both immunomodulatory ,, and antiangiogenic properties . IL-10 is expected to play a key role in limiting the host immune response during infection, inflammation, autoimmunity, transplantation, and tumorigenesis ,. IL-10 is also known as the cytokine synthesis inhibitory factor  which can inhibit the production of IL-1α, IL-1β, IL-6, IL-8, IL-12, and IL-18, as well as TNF-α and granulocyte macrophage-colony-stimulating factor in T cells and macrophage. In addition, IL-10 diminishes the expression of interferon (IFN)-γ in Th cells and peripheral blood mononuclear cells and stimulates the proliferation of mast cells.
| Interlukin-10 Signaling Pathways|| |
The receptor of IL-10 is a tetrameric transmembrane receptor complex containing two IL-10RA (also known as IL-10R1) and two IL-10RB (also known as IL-10R2) proteins . Both receptors are classified as class II cytokine (CRF2) family which is composed of an intracellular domain, a transmembrane domain, and an extracellular domain . IL-10RA has higher affinity for IL-10 than IL-10RB. IL-10 binds to the extracellular domain of IL-10RA and causes phosphorylation of Janus kinase-1 (JAK1) and tyrosine kinase-2 (TYK2). Once phosphorylated, JAK1 further phosphorylates the signal transducer and activator of transcription-3 (STAT3) and STAT3, then translocases to the nucleus, and turns on the transcription of anti-apoptotic and cell cycle-related genes . Conversely, STAT3 silencing and the suppressor of cytokine signaling 3 (SOCS3) protein reduces the expression of IL-10 . In addition to the JAK/STAT3 pathway, IL-10 activates the phosphoinositide 3-kinase (PI3K)/Akt/GSK3 β signaling cascade and modulates downstream transcription in macrophages ,. Moreover, IL-10 modulates mTOC1 activity in PI3K-mediated monocytes . Meanwhile, the activation of PI3K/Akt/mTOC1 and STAT3 pathways by IL-10 requires AMPK signaling . Notably, IL-10R activation also stimulates STAT1 and STAT5 pathways ,,,.
Along with IL-10, IL-6 is also involved in STAT3 activation [Figure 1]. Although pro-inflammatory and anti-inflammatory cytokines can work within the same cell or through the same signaling pathway, they perform very distinct functions and their downstream mechanisms are different ,,. A reasonable explanation may depend on the synergistic effect of STAT3 and other transcriptional cofactors that provide different gene expression programs. For example, in macrophages, both IL-10 and IL-6 induce the activation of SOCS3, but SCOS3 only inhibits the activity of IL-6R (gp130) ,. In addition, IL-10-stimulated-heme oxygenase 1 contributes to the anti-inflammatory response triggered by macrophages . Recently, Khan et al. found that SOCS3 and STAT-3 activities were regulated by downstream regulated gene 2 product (NDRG2) which suppresses IL-10 expression .
|Figure 1: Interleukin-10 signaling pathway. Binding of interleukin-10 to its receptor causes phosphorylation of JAK1 and TYK2. Once phosphorylated, JAK1 further phosphorylates signal transducer and activator of transcription-3 through AMPK. The signal transducer and activator of transcription-3 translocates into the nucleus and upregulates anti-inflammatory genes. Interleukin-10 also activates PI3K/Akt/mTOC pathway and inhibits GSK3β to promote anti-inflammatory responses. Interleukin-6, on the contrary, also activates signal transducer and activator of transcription-3 pathway. However, it upregulates pro-inflammatory genes and causes inflammatory response. The signal transducer and activator of transcription-3 signaling can be inhibited by the suppressor of cytokine signaling 3|
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| The Association of Interlukin-10 With Tumor-Associated Macrophage and Regulatory T Cells|| |
TAM has been found as the most abundant infiltrating leukocyte in most tumors and is thought to be correlated with a worse outcome in many tumors ,. TAM facilitates tumor progression by its immunosuppressive effects. Many immunosuppressive products such as IL-10, cathepsin B, and cathepsin S were produced by TAM in tumor sites . IL-10 produced by TAM has been reported to contribute to therapeutic resistance in BC including irradiation, chemotherapy, and immunotherapy . TAM-associated BC drug resistance is frequently associated with increased BCL2 expression and activation of STAT3 signaling . Because TAM may lead to therapeutic resistance, finding new and efficient therapies for BC is important. Currently, the use of IL-10 neutralizing antibody has been discussed and may be effective in TAM-induced BC. Tumor infiltrating Treg cells and macrophages were reported to be the origin of IL-10 production in murine tumor model . Therefore, chemotherapy-induced TAM which infiltrates the BC may recruit IL-10/IL-10R pathway and play a role in tumor pathogenesis. By targeting the IL-10 signaling pathway, we may expect a decreased therapeutic resistance and a better clinical outcome .
IL-10 brings into its immunosuppressive function at many aspects: suppression of T cell proliferation , modulation of APCs , and preservation of the activity/stability of Treg cells ,. It is still unclear about the effect of IL-10 on Treg cells, even though it is already known that IL-10 plays a major role in Treg suppression ,. A previous study indicated that IL-10 magnifies IL-10 expression (in a classic feedback loop regulation) on Treg cells via STAT3 activation, which, conversely, is significant for the inhibition of Th17 cell-induced inflammation . The role of IL-10 on Treg was also confirmed in another study with murine colitis model. When IL-10 is expressed on gut APCs, it preserves Foxp3 expression on Treg cells . There are two types of Treg cells: natural Treg (nTreg) and induced Treg (iTreg). nTreg cells are naturally produced in the thymus, whereas iTreg cells are produced when our immune response encounters a tumor antigen. However, most of the studies focused on the existed IL-10 on Treg but not in the course of iTreg production. Although the majority of Treg cells accumulating in tumors are nTreg cells, in some cases, iTreg cells are produced in spontaneous tumors or tumors without a defined tumor antigen . BC has an increased presence of Treg cells ,, yet little is known about the role of nTreg or iTreg cells in BC development. Fascinatingly, even though both IL-10 and IL-6 play different roles in inflammation, they deliver signals through STAT3 phosphorylation, with IL-6 being more crucial for the induction of Th17 cells  and detrimental for iTreg recruitment ,. However, the role of IL-10 in iTreg recruitment still remains controversial.
| Mechanism of Interlukin-10 in the Process of Breast Cancer and Other Tumors|| |
IL-10 paradoxically affects tumor development and pathogenesis . Currently, three biological activities of IL-10 that contribute to the pleiotropic effect have been revealed [Figure 2]. First, IL-10 can promote CD8+ T cell activation and proliferation, which has a direct or indirect cytotoxic effect on the cancer cells. Second, IL-10 inhibits T cell-stimulated tumor-killing immunity by suppressing antigen presentation by APCs. Lastly, IL-10 can inhibit tumor-promoting inflammation . Although high serum IL-10 is highly prevalent in end-stage cancer patients and correlates negatively with the survival , high IL-10 is generally accompanied by other cytokines and can dramatically affect the patients' overall immunity.
|Figure 2: Paradoxical effect of interleukin-10 on cancers. Interleukin-10 paradoxically affects tumor development by three pathways. First, interleukin-10 promotes CD4+ T cell activation and proliferation, which promote interferon-? secretion and induce tumor cell death. Next, interleukin-10 inhibits the effect of antigen-presenting cells, thereby allowing tumor cell to survive. At last, interleukin-10 can inhibit certain inflammatory cells and inhibit inflammation-related tumor cell growth|
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Both the pro- and anti-tumor effects of IL-10 have been well characterized . The role of IL-10 in modulating the immune response appears to depend on the TME and the number of IL-10 receptors expressed on the immune cells . Depleted IL-10 in mouse model has shown a positive relationship with the expression of inflammatory cytokine, IL-1, which facilitates tumor progression . IL-10 also suppresses the proliferation and activity of T cells  and therefore stimulates tumor cell proliferation and metastasis . Thence, IL-10 production can diminish cell-modulated inflammatory response in metastatic cancer cells  and can be a latent biomarker for human cancers in forecast and prognosis . Moreover, IL-10 shortage contributes to the rejection of ultraviolet-induced tumorigenesis . In addition, the expression of IL-10 mRNA is detected in >50% of BC samples . In many cancer patients, the existence of IL-10 in the TME has been depicted as a poor prognostic factor ,,. In addition, several evidences suggested a contrasting role for IL-10 in cancers. Both the expression and consumption of IL-10 have shown to be associated with tumor shrinkage and therapy resistance ,,. In contrast to the inhibition of cancer-facilitating inflammatory mediators (reviewed in ), IL-10 also promotes tumor angiogenesis .
The BC risk associated with chronic mastitis has been well documented . It appears that the toll-like receptors (TLRs) play a role in BC pathogenesis and recurrence ,,. TLRs can be activated through pathogen-associated molecular patterns (PAMPs) exogenously and endogenously, which, in turn, leads to the activation of inflammatory pathways . It was established that TLRs are highly expressed in BC samples ,,,, and is even higher in recurrence BC samples ,. Inflammatory markers such as serum C-reactive protein and amyloid A are correlated to poor clinical outcome in BC patients . TLR activation has an important role in IL-10 production. PAMPs can induce IL-10 production in macrophages by various pathways including TLR2/MSK/CREB and TPL2/ERK. The signaling pathways also produce type I IFNs, which promote IL-10 production and synergize with IL-10 in regulating downstream inflammatory process .
The function of IL-10 is controversial in BC. Studies investigating the relationship between IL-10 and BC are shown in [Table 1]. Overexpression of IL-10 leads to a defect in dominating and immunogenic tumors , while IL-10RA inhibition improves therapeutic outcome in BC model . Currently, very little is known about the in vitro function of IL-10 on the phenotypic conduct of BC cells, in terms of tumor cell migration and adherence to lymphatic and vessel endothelium. IL-10 has been reported to positively correlate with the overall survival rates in patients with colorectal cancer  and BC , but negatively correlate with patients with non-small cell lung carcinoma  and gastric cancer . In addition, higher serum IL-10 concentration was detected in BC patients than in healthy individuals [39, 81,104], which is correlated with a bad clinical outcome . It is indicated that IL-10 displayed an anti-metastatic function in murine model of BC and melanoma . One recent study showed that IL-10 suppresses MDA-MB-231 cell migration in a dose-dependent manner . The effect of IL-10 on MCF-7 cell was also observed in the same study, in which IL-10 can slightly but not significantly reduce the migration at 24 h after treatment. Because the migration rate of MDA-MB-231 is higher than that of MCF-7, a longer time would be required to observe the effect of IL-10 on MCF-7. IL-10 also causes immunosuppression by inducing TNF, IL-1, and IL-12 and certain chemokine production . In addition, IL-10 reduces the production of CD80 and CD86 which are the two co-stimulatory molecules on cancer cells. IL-10 refrains APCs uptaking tumor antigens  and provokes upregulation of certain factors which plays significant role in BC progression.  Administration of anti-tumor vaccine before IL-10 treatment has been shown to induce tumor development ,,,. IL-10 induces the production of tissues inhibitor of metalloproteinase and reduces the production of matrix metalloproteinase (MMP), thereby stimulating angiogenesis in BC . Treatment of IL-10 also accelerates inflammatory response by inducing the production of IFN-γ, IFN-γ-inducible protein-10 (IP-10, also known as CXCL10), and other monokines . As IL-10 promotes the progression of cancer cells, treatment with IL-10 antagonist may achieve a promising therapeutic efficacy and outcome .
| Mechanism of Interlukin-10 in Anti-Tumor Activity|| |
IL-10 in the TME has also been shown to correlate with anti-tumor immunity in both human and animal models. IL-10 exerts its anti-tumor effect by inhibiting angiogenesis . This anti-angiogenic effect was due to the reduction of vascular endothelial growth factor, TNF-α, IL-1β, IL-6, and MMP-9 . IL-10 can activate B cell differentiation into plasma cells which produce tumor cell-specific antibodies and mediate antibody-dependent cell cytotoxicity ,. IL-10 suppresses the translocation of nuclear factor-κB into the nucleus and inhibits the signaling for inflammation . IL-10 as well activates TILs and inhibits tumor development. Thence, IL-10 in the TME may protect tumor cell destruction by modulating host immune responses ,,,,. The contribution of IL-10 to the anticancer activity of NK cells is also well elucidated . IL-10 dose-dependently aided target cell vandalization by activating NK cells in an animal study , while another study demonstrated that IL-10 can activate CD4+ or CD8+ T cell to prevent the destruction of tumor cells . Therefore, IL-10 immunotherapy that modulates immunosuppression at the TME may be beneficial in treating BC and may be thought as a novel therapeutic approach . Accumulating successful of PEGylated IL-10 treatment to cancer models further supports the use of IL-10 immunotherapy in BC . IL-10 performs its anti-tumor function by enhancing the infiltration of CD8+ T cells in tissue, promoting T cell memory and upregulating IFN-γ expression ,. PEGylated IL-10 was therefore created  to stimulate such anti-tumor responses in cancer patients . Growing evidences point to the fact that IL-10 can promote tumor destruction and its potential can serve as a key agent for cancer patients' immunotherapy ,,.
| Interlukin-10 and Programmed Cell Death-1 Programmed Cell Death Ligand 1|| |
Programmed cell death-1 (PD-1) and programmed cell death ligand 1 (PD-L1) are known to inhibit anti-tumor immunity . Therefore, increasing attention has been focused on treating cancers with therapeutic PD-1 and PD-L1 antibodies. Studies concerning the release of IL-10 in patients resisting anti-PD-1/anti-PD-L1 monotherapies revealed that IL-10 is linked to PD-1/PD-L1 signaling pathways. Blockage of PD-1 and IL-10 improves the survival by reducing tumor burden and augments anti-tumor immune responses . Pembrolizumab (PD-1 inhibitor) and atezolizumab (PD-L1 inhibitor) are two immune checkpoint inhibitors that are heavily utilized in BC immunotherapy. The use of a single inhibitor has shown to produce durable responses and favorable survival in TNBC patients ,. The inhibitors are also augmented with chemotherapy agents such as nanoparticle albumin-bound paclitaxel (nab-paclitaxel) to treat PD-L1+ patients with metastatic TNBC . Neoadjuvant chemotherapy, when combined with cytotoxic chemotherapy, achieves higher rates of pathological complete response and significantly increases the event-free survival . Several literatures have already suggested that IL-10 and PD-1 pathways intersect in many cancers ,. Considering that IL-10 could paradoxically affect patients' immune responses, combination therapy that target IL-10 signaling to augment immune responses is compelling.
| Conclusion|| |
One characteristic feature of BC is immune infiltration. Although the TME of BC is constantly immunosuppressive, infiltrated immune cells can exhibit both pro- and anti-tumor activities. IL-10 is one of the cytokines produced by these immune cells and displays both tumor-promoting and -inhibiting activities. A broad range of IL-10-expressing and IL-10-replying cells take part in modulating the immune response under different circumstances and at different sites. However, the opposing effects of IL-10 make therapeutic manipulation challenging. A profound comprehension of the molecular mechanisms and cellular functions of IL-10 may enable us to design potential therapeutic agents to manipulate IL-10-related immune response to tumor cells. At last, the use of IL-10 agonists and antagonists may have advantages in treating BC.
Financial support and sponsorship
SJJ and HJH acknowledge the Tzu Chi University (TCMRC-P-108010) for financial support.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Hon JD, Singh B, Sahin A, Du G, Wang J, Wang VY, et al. Breast cancer molecular subtypes: From TNBC to QNBC. Am J Cancer Res 2016;6:1864-72.
Podo F, Buydens LM, Degani H, Hilhorst R, Klipp E, Gribbestad IS, et al. Triple-negative breast cancer: Present challenges and new perspectives. Mol Oncol 2010;4:209-29.
Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 2008;26:1275-81.
Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med 2010;363:1938-48.
Naga Anusha P, Aliya S, Hima Bindu A. Immuno defense mechanism against tumors. J Cancer Sci Ther 2011;S17. [Doi: 10.4172/1948-5956.S17-005].
Dietrich PY, Walker PR. Échappement et tolérance des tumeurs É l'apoptose. Tumour Toler Immune Escape Apoptosis 2000;16:492.
Maimela NR, Liu S, Zhang Y. Fates of CD8+ T cells in tumor microenvironment. Comput Struct Biotechnol J 2019;17:1-3.
Galaine J, Borg C, Godet Y, Adotévi O. Interest of tumor-specific CD4 T helper 1 cells for therapeutic anticancer vaccine. Vaccines (Basel) 2015;3:490-502.
Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L,
et al. Polarization of tumor-associated neutrophil (TAN) phenotype by TGF-β: “N1” versus “N2” TAN. Cancer Cell 2009;16:183-94.
Mohammed RA, Ellis IO, Elsheikh S, Paish EC, Martin SG. Lymphatic and angiogenic characteristics in breast cancer: Morphometric analysis and prognostic implications. Breast Cancer Res Treat 2009;113:261-73.
Mohammed RA, Menon S, Martin SG, Green AR, Paish EC, Ellis IO. Prognostic significance of lymphatic invasion in lymph node-positive breast carcinoma: Findings from a large case series with long-term follow-up using immunohistochemical endothelial marker. Mod Pathol 2014;27:1568-77.
Mohammed ZM, Going JJ, Edwards J, Elsberger B, Doughty JC, McMillan DC. The relationship between components of tumour inflammatory cell infiltrate and clinicopathological factors and survival in patients with primary operable invasive ductal breast cancer. Br J Cancer 2012;107:864-73.
Pollard JW. Macrophages define the invasive microenvironment in breast cancer. J Leukoc Biol 2008;84:623-30.
Loi S, Drubay D, Adams S, Pruneri G, Francis PA, Lacroix-Triki M, et al. Tumor-infiltrating lymphocytes and prognosis: A pooled individual patient analysis of early-stage triple-negative breast cancers. J Clin Oncol 2019;37:559-69.
Miksch RC, Schoenberg MB, Weniger M, Bösch F, Ormanns S, Mayer B, et al. Prognostic impact of tumor-infiltrating lymphocytes and neutrophils on survival of patients with upfront resection of pancreatic cancer. Cancers (Basel) 2019;11:39.
Lee N, Zakka LR, Mihm MC Jr., Schatton T. Tumour-infiltrating lymphocytes in melanoma prognosis and cancer immunotherapy. Pathology 2016;48:177-87.
Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW. The prognostic influence of tumour-infiltrating lymphocytes in cancer: A systematic review with meta-analysis. Br J Cancer 2011;105:93-103.
Guillerey C, Huntington ND, Smyth MJ. Targeting natural killer cells in cancer immunotherapy. Nat Immunol 2016;17:1025-36.
Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010;140:883-99.
Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL, et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol 2006;24:5373-80.
Bohling SD, Allison KH. Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: A potential therapeutic target. Mod Pathol 2008;21:1527-32.
Ohara M, Yamaguchi Y, Matsuura K, Murakami S, Arihiro K, Okada M. Possible involvement of regulatory T cells in tumor onset and progression in primary breast cancer. Cancer Immunol Immunother 2009;58:441-7.
Joshi NS, Akama-Garren EH, Lu Y, Lee DY, Chang GP, Li A, et al. Regulatory T cells in tumor-associated tertiary lymphoid structures suppress anti-tumor t cell responses. Immunity 2015;43:579-90.
Klages K, Mayer CT, Lahl K, Loddenkemper C, Teng MW, Ngiow SF, et al. Selective depletion of Foxp3+ regulatory T cells improves effective therapeutic vaccination against established melanoma. Cancer Res 2010;70:7788-99.
Pastille E, Bardini K, Fleissner D, Adamczyk A, Frede A, Wadwa M, et al. Transient ablation of regulatory T cells improves antitumor immunity in colitis-associated colon cancer. Cancer Res 2014;74:4258-69.
Teng MW, Ngiow SF, von Scheidt B, McLaughlin N, Sparwasser T, Smyth MJ. Conditional regulatory T-cell depletion releases adaptive immunity preventing carcinogenesis and suppressing established tumor growth. Cancer Res 2010;70:7800-9.
Bos PD, Plitas G, Rudra D, Lee SY, Rudensky AY. Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy. J Exp Med 2013;210:2435-66.
Gobert M, Treilleux I, Bendriss-Vermare N, Bachelot T, Goddard-Leon S, Arfi V, et al. Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res 2009;69:2000-9.
Hossain DM, Panda AK, Manna A, Mohanty S, Bhattacharjee P, Bhattacharyya S, et al. FoxP3 acts as a cotranscription factor with STAT3 in tumor-induced regulatory T cells. Immunity 2013;39:1057-69.
Senovilla L, Vitale I, Martins I, Tailler M, Pailleret C, Michaud M,
et al. An immunosurveillance mechanism controls cancer cell ploidy. Science 2012;337:1678-84.
Shang B, Liu Y, Jiang SJ, Liu Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: A systematic review and meta-analysis. Sci Rep 2015;5:15179.
Paluskievicz CM, Cao X, Abdi R, Zheng P, Liu Y, Bromberg JS. T regulatory cells and priming the suppressive tumor microenvironment. Front Immunol 2019;10:2453.
Ohue Y, Nishikawa H. Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? Cancer Sci 2019;110:2080-9.
Sheikhpour R, Mohiti J. The effect of progesterone on p53 in T47D cell line. Urmia J Med Sci 2014;25:954-60.
Acuner-Ozbabacan ES, Engin BH, Guven-Maiorov E, Kuzu G, Muratcioglu S, Baspinar A, et al. The structural network of Interleukin-10 and its implications in inflammation and cancer. BMC Genomics 2014;15(Suppl 4):S2.
Abdolrahim-Zadeh H, Hakkakian N, Asadollahi R, Gharesifard B, Sarvari J, Eskandar Kamali-Sarvestani E. Interleukin-10 promoter polymorphisms and breast cancer risk in Iranian women. Iran J Immunol 2005;2:158-65.
Howell MW. Interleukin-10 gene polymorphisms and cancer. Madame Curie Bioscience Database. Landes Bioscience 2000;8:2013-5.
Khan H, Changkija B, Konwar R. Role of interleukin-10 in breast cancer. Breast Cancer Res Treat 2012;133:11-21.
Sung WW, Lee H. The role of interleukin-10 in the progression of human papillomavirus-associated lung carcinoma. Oncoimmunology 2013;2:e25854.
Kong F, Liu J, Liu Y, Song B, Wang H, Liu W. Association of interleukin-10 gene polymorphisms with breast cancer in a Chinese population. J Exp Clin Cancer Res 2010;29:72.
Gerger A, Renner W, Langsenlehner T, Hofmann G, Knechtel G, Szkandera J, et al. Association of interleukin-10 gene variation with breast cancer prognosis. Breast Cancer Res Treat 2010;119:701-5.
Pooja S, Chaudhary P, Nayak LV, Rajender S, Singh Saini D. Polymorphic variations in IL-1b, IL-6 and IL-10 genes, their circulating serum levels and breast cancer risk in Indian women. Cytokine 2012;60:122-8.
Kim J, Modlin RL, Moy RL, Dubinett SM, McHugh T, Nickoloff BJ, et al. IL-10 production in cutaneous basal and squamous cell carcinomas. A mechanism for evading the local T cell immune response. J Immunol 1995;155:2240-7.
Fortis C, Foppoli M, Gianotti L, Galli L, Citterio G, Consogno G, et al. Increased interleukin-10 serum levels in patients with solid tumours. Cancer Lett 1996;104:1-5.
Crawley JB, Williams LM, Mander T, Brennan FM, Foxwell BM. Interleukin-10 stimulation of phosphatidylinositol 3-kinase and p70 S6 kinase is required for the proliferative but not the antiinflammatory effects of the cytokine. J Biol Chem 1996;271:16357-62.
Antoniv TT, Ivashkiv LB. Interleukin-10-induced gene expression and suppressive function are selectively modulated by the PI3KAkt-GSK3 pathway. Immunology 2011;132:567-77.
Zhu YP, Brown JR, Sag D, Zhang L, Suttles J. Adenosine 5'-monophosphate-activated protein kinase regulates IL-10-mediated anti-inflammatory signaling pathways in macrophages. J Immunol 2015;194:584-94.
Lehmann J, Seegert D, Strehlow I, Schindler C, Lohmann-Matthes ML, Decker T. IL-10-induced factors belonging to the p91 family of proteins bind to IFN-gamma-responsive promoter elements. J Immunol 1994;153:165-72.
Wehinger J, Gouilleux F, Groner B, Finke J, Mertelsmann R, Weber-Nordt RM. IL-10 induces DNA binding activity of three STAT proteins (Stat1, Stat3, and Stat5) and their distinct combinatorial assembly in the promoters of selected genes. FEBS Lett 1996;394:365-70.
Rahimi AA, Gee K, Mishra S, Lim W, Kumar A. STAT-1 mediates the stimulatory effect of IL-10 on CD14 expression in human monocytic cells. J Immunol 2005;174:7823-32.
Emmerich J, Mumm JB, Chan IH, LaFace D, Truong H, McClanahan T, et al. IL-10 directly activates and expands tumor-resident CD8(+) T cells without de novo infiltration from secondary lymphoid organs. Cancer Res 2012;72:3570-81.
Murray PJ. STAT3-mediated anti-inflammatory signalling. Biochem Soc Trans 2006;34:1028-31.
Murray PJ. The JAK-STAT signaling pathway: Input and output integration. J Immunol 2007;178:2623-9.
Hutchins AP, Diez D, Miranda-Saavedra D. The IL-10/STAT3-mediated anti-inflammatory response: Recent developments and future challenges. Brief Funct Genomics 2013;12:489-98.
Croker BA, Krebs DL, Zhang JG, Wormald S, Willson TA, Stanley EG, et al. SOCS3 negatively regulates IL-6 signaling in vivo
. Nat Immunol 2003;4:540-5.
Lang R, Pauleau AL, Parganas E, Takahashi Y, Mages J, Ihle JN, et al. SOCS3 regulates the plasticity of gp130 signaling. Nat Immunol 2003;4:546-50.
Lee TS, Chau LY. Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice. Nat Med 2002;8:240-6.
Chen Y, Song Y, Du W, Gong L, Chang H, Zou Z. Tumor-associated macrophages: An accomplice in solid tumor progression. J Biomed Sci 2019;26:78.
Lin Y, Xu J, Lan H. Tumor-associated macrophages in tumor metastasis: Biological roles and clinical therapeutic applications. J Hematol Oncol 2019;12:76.
Wang R, Lu M, Zhang J, Chen S, Luo X, Qin Y,
et al. Increased IL-10 mRNA expression in tumor-associated macrophage correlated with late stage of lung cancer. J Exp Clin Cancer Res 2011;30:62.
Jiang X. Macrophage-produced IL-10 limits the chemotherapy efficacy in breast cancer. J Zhejiang Univ Sci B 2015;16:44-5.
Yang C, He L, He P, Liu Y, Wang W, He Y. Increased drug resistance in breast cancer by tumor-associated macrophages through IL-10/STAT3/bcl-2 signaling pathway. Med Oncol 2015;32:352-5.
Deng G. Tumor-infiltrating regulatory T cells: Origins and features. Am J Clin Exp Immunol 2018;7:81-7.
de Waal Malefyt R, Yssel H, de Vries JE. Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. J Immunol 1993;150:4754-65.
de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de Vries JE. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: An autoregulatory role of IL-10 produced by monocytes. J Exp Med 1991;174:1209-20.
Chaudhry A, Samstein RM, Treuting P, Liang Y, Pils MC, Heinrich JM, et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 2011;34:566-78.
Murai M, Turovskaya O, Kim G, Madan R, Karp CL, Cheroutre H, et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol 2009;10:1178-84.
Rubtsov YP, Rasmussen JP, Chi EY, Fontenot J, Castelli L, Ye X, et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 2008;28:546-58.
Miyara M, Sakaguchi S. Natural regulatory T cells: Mechanisms of suppression. Trends Mol Med 2007;13:108-16.
Schreiber TH, Wolf D, Bodero M, Podack E. Tumor antigen specific iTreg accumulate in the tumor microenvironment and suppress therapeutic vaccination. Oncoimmunology 2012;1:642-8.
Ha TY. The role of regulatory T cells in cancer. Immune Netw 2009;9:209-35.
Plitas G, Konopacki C, Wu K, Bos PD, Morrow M, Putintseva EV, et al. Regulatory T Cells Exhibit Distinct Features in Human Breast Cancer. Immunity 2016;45:1122-34.
Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, et al. IL-6 programs T (H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 2007;8:967-74.
Fujimoto M, Nakano M, Terabe F, Kawahata H, Ohkawara T, Han Y, et al. The influence of excessive IL-6 production in vivo
on the development and function of Foxp3+regulatory T cells. J Immunol 2011;186:32-40.
Doganci A, Eigenbrod T, Krug N, De Sanctis GT, Hausding M, Erpenbeck VJ, et al. The IL-6R alpha chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo
. J Clin Invest 2005;115:313-25.
Mannino MH, Zhu Z, Xiao H, Bai Q, Wakefield MR, Fang Y. The paradoxical role of IL-10 in immunity and cancer. Cancer Lett 2015;367:103-7.
Ouyang W, O'Garra A. IL-10 Family Cytokines IL-10 and IL-22: From Basic Science to Clinical Translation. Immunity 2019;50:871-91.
Lippitz BE. Cytokine patterns in patients with cancer: A systematic review. Lancet Oncol 2013;14:e218-28.
Zhao S, Wu D, Wu P, Wang Z, Huang J. Serum IL-10 predicts worse outcome in cancer patients: A meta-analysis. PLoS One 2015;10:e0139598.
Dennis KL, Blatner NR, Gounari F, Khazaie K. Current status of interleukin-10 and regulatory T-cells in cancer. Curr Opin Oncol 2013;25:637-45.
Llanes-Fernández L, Alvarez-Goyanes RI, Arango-Prado Mdel C, Alcocer-González JM, Mojarrieta JC, Pérez XE, et al. Relationship between IL-10 and tumor markers in breast cancer patients. Breast 2006;15:482-9.
Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001;19:683-765.
Chang CM, Lin MC, Yin WY. Risk of breast cancer in women with non-lactational mastitis. Sci Rep 2019;9:15587.
Loser K, Apelt J, Voskort M, Mohaupt M, Balkow S, Schwarz T, et al. IL-10 controls ultraviolet-induced carcinogenesis in mice. J Immunol 2007;179:365-71.
Venetsanakos E, Beckman I, Bradley J, Skinner JM. High incidence of interleukin 10 mRNA but not interleukin 2 mRNA detected in human breast tumours. Br J Cancer 1997;75:1826-30.
Nemunaitis J, Fong T, Shabe P, Martineau D, Ando D. Comparison of serum interleukin-10 (IL-10) levels between normal volunteers and patients with advanced melanoma. Cancer Invest 2001;19:239-47.
O'Garra A, Barrat FJ, Castro AG, Vicari A, Hawrylowicz C. Strategies for use of IL-10 or its antagonists in human disease. Immunol Rev 2008;223:114-31.
Berman RM, Suzuki T, Tahara H, Robbins PD, Narula SK, Lotze MT. Systemic administration of cellular IL-10 induces an effective, specific, and long-lived immune response against established tumors in mice. J Immunol 1996;157:231-8.
Zheng LM, Ojcius DM, Garaud F, Roth C, Maxwell E, Li Z, et al. Interleukin-10 inhibits tumor metastasis through an NK cell-dependent mechanism. J Exp Med 1996;184:579-84.
Groux H, Cottrez F, Rouleau M, Mauze S, Antonenko S, Hurst S, et al. A transgenic model to analyze the immunoregulatory role of IL-10 secreted by antigen-presenting cells. J Immunol 1999;162:1723-9.
Sakamoto T, Saito H, Tatebe S, Tsujitani S, Ozaki M, Ito H, et al. Interleukin-10 expression significantly correlates with minor CD8+ T-cell infiltration and high microvessel density in patients with gastric cancer. Int J Cancer 2006;118:1909-14.
Jukkola-Vuorinen A, Rahko E, Vuopala KS, Desmond R, Lehenkari PP, Harris KW, et al. Toll-like receptor-9 expression is inversely correlated with estrogen receptor status in breast cancer. J Innate Immun 2009;1:59-68.
Amarante MK, de Oliveira KB, Guembarovski RL, da Silva do Amaral Herrera AC, Guembarovski AL, Sobrinho WJ, et al. Toll-like receptor 3: Implications for proinflammatory microenvironment in human breast cancer. Mol Biol Rep 2012;39:11087-92.
Bhatelia K, Singh K, Singh R. TLRs: Linking inflammation and breast cancer. Cell Signal 2014;26:2350-7.
Liao SJ, Zhou YH, Yuan Y, Li D, Wu FH, Wang Q, et al. Triggering of Toll-like receptor 4 on metastatic breast cancer cells promotes αvβ3-mediated adhesion and invasive migration. Breast Cancer Res Treat 2012;133:853-63.
Ehsan N, Murad S, Ashiq T, Mansoor MU, Gul S, Khalid S, et al. Significant correlation of TLR4 expression with the clinicopathological features of invasive ductal carcinoma of the breast. Tumour Biol 2013;34:1053-9.
Pierce BL, Ballard-Barbash R, Bernstein L, Baumgartner RN, Neuhouser ML, Wener MH, et al. Elevated biomarkers of inflammation are associated with reduced survival among breast cancer patients. J Clin Oncol 2009;27:3437-44.
Li Y, Yu H, Jiao S, Yang J. Prognostic value of IL-10 expression in tumor tissues of breast cancer patients. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2014;30:517-20.
Kundu N, Beaty TL, Jackson MJ, Fulton AM. Antimetastatic and antitumor activities of interleukin 10 in a murine model of breast cancer. J Natl Cancer Inst 1996;88:536-41.
Li Y, Gao P, Yang J, Yu H, Zhu Y, Si W. Relationship between IL-10 expression and prognosis in patients with primary breast cancer. Tumour Biol 2014;35:11533-40.
Giovarelli M, Musiani P, Modesti A, Dellabona P, Casorati G, Allione A, et al. Local release of IL-10 by transfected mouse mammary adenocarcinoma cells does not suppress but enhances antitumor reaction and elicits a strong cytotoxic lymphocyte and antibody-dependent immune memory. J Immunol 1995;155:3112-23.
Di Carlo E, Coletti A, Modesti A, Giovarelli M, Forni G, Musiani P. Local release of interleukin-10 by transfected mouse adenocarcinoma cells exhibits pro- and anti-inflammatory activity and results in a delayed tumor rejection. Eur Cytokine Netw 1998;9:61-8.
Kozłowski L, Zakrzewska I, Tokajuk P, Wojtukiewicz MZ. Concentration of interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-10 (IL-10) in blood serum of breast cancer patients. Rocz Akad Med Bialymst 2003;48:82-4.
Mohamed HT, El-Husseiny N, El-Ghonaimy EA, Ibrahim SA, Bazzi ZA, Cavallo-Medved D, et al. IL-10 correlates with the expression of carboxypeptidase B2 and lymphovascular invasion in inflammatory breast cancer: The potential role of tumor infiltrated macrophages. Curr Probl Cancer 2018;42:215-30.
Woo SU, Bae JW, Yang JH, Kim JH, Nam SJ, Shin YK. Overexpression of interleukin-10 in sentinel lymph node with breast cancer. Ann Surg Oncol 2007;14:3268-73.
Pusztai L, Mendoza TR, Reuben JM, Martinez MM, Willey JS, Lara J, et al. Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy. Cytokine 2004;25:94-102.
Chavey C, Bibeau F, Gourgou-Bourgade S, Burlinchon S, Boissière F, Laune D, et al. Oestrogen receptor negative breast cancers exhibit high cytokine content. Breast Cancer Res 2007;9:R15.
Son KS, Kang HS, Kim SJ, Jung SY, Min SY, Lee SY, et al. Hypomethylation of the interleukin-10 gene in breast cancer tissues. Breast 2010;19:484-8.
Sato T, Terai M, Tamura Y, Alexeev V, Mastrangelo MJ, Selvan SR. Interleukin 10 in the tumor microenvironment: A target for anticancer immunotherapy. Immunol Res 2011;51:170-82.
Heckel MC, Wolfson A, Slachta CA, Schwarting R, Salgame P, Katsetos CD,
et al. Human breast tumor cells express IL-10 and IL-12p40 transcripts and proteins, but do not produce IL-12p70. Cell Immunol 2011;266:143-53.
Rao VS, Alabi A, Dyer CE, Greenman J, Drew PJ. IL-10 and IL-12 Expression in Breast Cancer Patients and Effect of Therapy. ASCO Annual Meeting Proceedings; 2008.
Hagenbaugh A, Sharma S, Dubinett SM, Wei SH, Aranda R, Cheroutre H, et al. Altered immune responses in interleukin 10 transgenic mice. J Exp Med 1997;185:2101-10.
Ruffell B, Chang-Strachan D, Chan V, Rosenbusch A, Ho CM, Pryer N, et al. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell 2014;26:623-37.
Toiyama Y, Miki C, Inoue Y, Minobe S, Urano H, Kusunoki M. Loss of tissue expression of interleukin-10 promotes the disease progression of colorectal carcinoma. Surg Today 2010;40:46-53.
Hatanaka H, Abe Y, Kamiya T, Morino F, Nagata J, Tokunaga T, et al. Clinical implications of interleukin (IL)-10 induced by non-small-cell lung cancer. Ann Oncol 2000;11:815-9.
Visco C, Vassilakopoulos TP, Kliche KO, Nadali G, Viviani S, Bonfante V. Elevated serum levels of IL–10 are associated with inferior progression-free survival in patients with Hodgkin's disease treated with radiotherapy. Leuk Lymphoma 2004;45:2085-92.
Ahmad N, Ammar A, Storr SJ, Green AR, Rakha E, Ellis IO, et al. IL-6 and IL-10 are associated with good prognosis in early stage invasive breast cancer patients. Cancer Immunol Immunother 2018;67:537-49.
Vinod C, Jyothy A, Vijay Kumar M, Raman RR, Nallari P, Venkateshwari A. A common SNP of IL-10 (-1082A/G) is associated with increased risk of premenopausal breast cancer in South Indian Women. Iran J Cancer Prev 2015;8:e3434.
Beckebaum S, Zhang X, Chen X, Yu Z, Frilling A, Dworacki G. Increased levels of interleukin-10 in serum from patients with hepatocellular carcinoma correlate with profound numerical deficiencies and immature phenotype of circulating dendritic cell subsets. Clin Canc Res 2004;10: 7260-71.
Fujii S, Shimizu K, Shimizu T, Lotze MT. Interleukin-10 promotes the maintenance of antitumor CD8(+) T-cell effector function in situ. Blood 2001;98:2143-51.
Mocellin S, Panelli MC, Wang E, Nagorsen D, Marincola FM. The dual role of IL-10. Trend Immunol 2003;24:36-44.
Mumm JB, Oft M. Pegylated IL-10 induces cancer immunity: The surprising role of IL-10 as a potent inducer of IFN-γ-mediated CD8(+) T cell cytotoxicity. Bioessays 2013;35:623-31.
Alexandrakis MG, Goulidaki N, Pappa CA, Boula A, Psarakis P, Neonakis F,
et al. Interleukin-10 Induces Both Plasma Cell Proliferation and Angiogenesis in Multiple Myeloma. Pathol Oncol Res 2015;21:929-34.
Sharonov GV, Serebrovskaya EO, Yuzhakova DV, Britanova OV, Chudakov DM. B cells, plasma cells and antibody repertoires in the tumour microenvironment. Nat Rev Immunol 2020;20:294-307.
Mumm JB, Emmerich J, Zhang X, Chan I, Wu L, Mauze S,
et al. IL-10 elicits IFN-γ-dependent tumor immune surveillance. Cancer Cell 2011;20:781-96.
Naing A, Papadopoulos KP, Autio KA, Ott PA, Patel MR, Wong DJ, et al. Safety, antitumor activity, and immune activation of pegylated recombinant human interleukin-10 (AM0010) in patients with advanced solid tumors. J Clin Oncol 2016;34:3562-9.
Naing A, Infante JR, Papadopoulos KP, Chan IH, Shen C, Ratti NP, et al. PEGylated IL-10 (Pegilodecakin) induces systemic immune activation, CD8+ T cell invigoration and polyclonal T cell expansion in cancer patients. Cancer Cell 2018;34:775-91000.
Autio K, Oft M. Pegylated interleukin-10: Clinical development of an immunoregulatory cytokine for use in cancer therapeutics. Curr Oncol Rep 2019;21:19.
Wang X, Wong K, Ouyang W, Rutz S. Targeting IL-10 family cytokines for the treatment of human diseases. Cold Spring Harb Perspect Biol 2019;11:a028548.
Lamichhane P, Karyampudi L, Shreeder B, Krempski J, Bahr D, Daum J, et al. IL10 release upon PD-1 blockade sustains immunosuppression in ovarian cancer. Cancer Res 2017;77:6667-78.
Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: Phase Ib KEYNOTE-012 study. J Clin Oncol 2016;34:2460-7.
Emens LA, Cruz C, Eder JP, Braiteh F, Chung C, Tolaney SM, et al. Long-term clinical outcomes and biomarker analyses of atezolizumab therapy for patients with metastatic triple-negative breast cancer: A phase 1 study. JAMA Oncol 2019;5:74-82.
Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med 2020;382:810-21.
Han Y, Liu D, Li L. PD-1/PD-L1 pathway: Current researches in cancer. Am J Cancer Res 2020;10:727-42.
Jiang X, Wang J, Deng X, Xiong F, Ge J, Xiang B, et al. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol Cancer 2019;18:10.
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