Interleukin-35 Limits Anti-Tumor Immunity

Turnis, Meghan E.; Sawant, Deepali V.; Szymczak-Workman, Andrea L.; Andrews, Lawrence P.; Delgoffe, Greg M.; Yano, Hiroshi; Beres, Amy; Vogel, Peter; Workman, Creg J.; Vignali, Dario A.A.

doi:10.1016/j.immuni.2016.01.013

Cited by 249 publications

(258 citation statements)

References 39 publications

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“…There are four mechanisms by which T regs suppress responder T cells [20][21][22][23][24]. First, T regs secrete inhibitory cytokines such as interleukin (IL)-35, IL-10 and transforming growth factor (TGF)-b to inhibit T cells directly.…”

Section: Introductionmentioning

confidence: 99%

Ovarian cancer stem cells promote tumour immune privilege and invasion via CCL5 and regulatory T cells

You

et al. 2017

Clinical and Experimental Immunology

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SummaryEmerging evidence indicates a link between the increased proportion of regulatory T cells (T regs ) and reduced survival in patients who have been diagnosed with cancer. Cancer stem cells (CSCs) have been indicated to play a vital role in tumour initiation, drug resistance and recurrence. However, the relationship between T regs and CSCs remains largely unknown. Here, we sorted out ovarian cancer stem-like side population (SP) cells and CD133 1 cells to investigate the influence of ovarian CSCs on T regs . Among the various immune-related molecules that we assessed, C-C motif chemokine ligand 5 (CCL5) was the most elevated in ovarian CSCs relative to that in the non-CSCs. The expression of its receptor, C-C motif chemokine receptor 5 (CCR5), was also increased on the surface of T regs in ovarian cancer patients. This receptor-ligand expression profile indicated that ovarian CSCs recruit T regs via CCL5-CCR5 interactions. We further assessed the expression of interleukin (IL)-10 in T regs cultured with different cancer cells. For the first time, to our knowledge, our findings describe the relationship between ovarian CSCs and T regs , and demonstrated that these two cell populations co-operate to promote tumour immune tolerance and enhance tumour progression.

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Section: Introductionmentioning

confidence: 99%

Ovarian cancer stem cells promote tumour immune privilege and invasion via CCL5 and regulatory T cells

You

et al. 2017

Clinical and Experimental Immunology

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“…When artificially over-expressed in transplanted cancer cells, IL-35 promotes myeloid cell accumulation and angiogenesis in both immune-competent and -deficient mice . Antibody-mediated depletion of IL-35 in mice enhanced immunity against multiple human cancers in mice (Turnis et al, 2016). Treg-derived IL-35 promotes the expression of PD1, TIM3, and LAG3, and facilitates T cell exhaustion (Turnis et al, 2016).…”

Section: Interleukin-35mentioning

confidence: 99%

Regulatory T Cells and Cancer: A Two-Sided Story

Wang

Vella

2016

Immunological Investigations

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Regulatory T cells (Tregs) play pivotal roles in limiting the duration and magnitude of immune response against infectious agents and self-antigens. This is accomplished through contact-dependent and -independent mechanisms that involve crosstalk between Treg cells and other immune and tissue-specific cell types. The same machinery is employed by Tregs to regulate immune responses to cancer, limiting both pro-tumor inflammation and anti-tumor immunity. Factors produced by Treg cells also act directly on transformed epithelial cells and exert opposing effects during different stages of cancer development. Therefore, the immune regulatory cell population serves as a double-edged sword for the development, progression, and treatment of cancers. In this review, we summarize current knowledge on the roles of Treg lymphocytes during cancer development, as well as the underlying cellular and molecular mechanism.

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“…IL-35 has anti-inflammatory and immunoregulatory properties [9,11], and inhibits angiogenesis through different signaling pathways [12]. It also plays pivotal roles in the pathogenesis of cancers, as it promotes the growth of cancer cells through the enhancement of proliferation and angiogenesis, inhibition of apoptosis [13][14][15], and limitation of anti-tumor T cells immunity [16]. In addition, elevated IL-35 levels are also associated with cancer progression, aggressiveness, and recurrence [17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Interleukin-35 Suppresses the Antitumor Activity of T Cells in Patients with Non-Small Cell Lung Cancer

Wang¹,

Zhang²,

Feng³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Interleukin (IL)-35 has immunosuppressive functions in autoimmune diseases, infectious diseases, and certain cancers. However, few studies have focused on its immunoregulatory activity in non-small cell lung cancer (NSCLC). Thus, we investigated the role of IL-35 in the pathogenesis of this disease. Methods: A total of 66 NSCLC patients and 21 healthy individuals were enrolled. IL-35 expression in peripheral blood and bronchoalveolar lavage fluid (BALF) was measured. The modulatory functions of IL-35 on purified CD4⁺ and CD8⁺ T cells from NSCLC patients were investigated in direct and indirect coculture systems with NSCLC cell lines. Results: IL-35 expression was significantly increased in BALF from the tumor site, but not in the peripheral blood of NSCLC patients. IL-35 did not affect the bioactivity including proliferation, cytokine production, cell cycle, and cellular invasion of NSCLC cells. It suppressed responses from type 1 T helper (Th1) and Th17 cells but elevated the regulatory T cell response in cultured CD4⁺ T cells from NSCLC patients, and reduced cytokine-mediated CD4⁺ T cells cytotoxicity to NSCLC cells. Moreover, IL-35 also inhibited cytotoxic gene expression in CD8⁺ T cells from NSCLC, reducing their cytolytic and noncytolytic functions. Conclusion: The results of this study suggest that IL-35 contributes to the dysfunction/exhaustion of T cells and limited antitumor immune responses in NSCLC.

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Interleukin-35 Limits Anti-Tumor Immunity

Cited by 249 publications

References 39 publications

Ovarian cancer stem cells promote tumour immune privilege and invasion via CCL5 and regulatory T cells

Ovarian cancer stem cells promote tumour immune privilege and invasion via CCL5 and regulatory T cells

Regulatory T Cells and Cancer: A Two-Sided Story

Interleukin-35 Suppresses the Antitumor Activity of T Cells in Patients with Non-Small Cell Lung Cancer

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