Interleukin-10 receptor signaling promotes the maintenance of a PD-1int TCF-1+ CD8+ T cell population that sustains anti-tumor immunity

Hanna, Bola S.; Llaó-Cid, Laura; Iskar, Murat; Roessner, Philipp M.; Klett, Lara; Wong, John; Paul, Yashna; Ioannou, Nikolaos; Öztürk, Selcen; Mack, Norman; Kalter, Verena; Colomer, Dolors; Campo, Elı́as; Bloehdorn, Johannes; Stilgenbauer, Stephan; Dietrich, Sascha; Schmidt, Manfred; Rinaldi, Gabriel; Rippe, Karsten; Feuerer, Markus; Ramsay, Alan G.; Lichter, Peter; Zapatka, Marc; Seiffert, Martina

doi:10.1016/j.immuni.2021.11.004

Cited by 73 publications

(56 citation statements)

References 113 publications

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“…Thus, it is unlikely that IL-10 signaling is directly exploited by viral factors to promote the survival of a productively infected host cell, but rather it nonspecifically supports the homeostasis and long-term maintenance of a pool of target cells that contribute to viral persistence with long-term ART. If extrapolated beyond CD4 + T cells, our results on IL-10 signaling supporting the long-term maintenance of immunological memory may help explain recent data showing that IL-10R signaling favors the maintenance of a population of CD8 + T cells that promote tumor control in oncology models ( 57 ). Thus, our data suggest that IL-10 colocalization supports survival of T cells, including those harboring SIV-DNA, in immune-privileged anatomic niches of viral persistence during ART, such as the LN BCF ( 6 , 58 ).…”

Section: Discussionsupporting

confidence: 58%

Interleukin-10 contributes to reservoir establishment and persistence in SIV-infected macaques treated with antiretroviral therapy

Harper¹,

Ribeiro²,

Chan³

et al. 2022

Journal of Clinical Investigation

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Interleukin (IL)-10 is an immunosuppressive cytokine that signals through STAT3 to regulate T follicular helper cell (TFH) differentiation and germinal center formation. In SIV-infected macaques, levels of IL-10 in plasma and lymph node (LN) were induced by infection and not normalized with ART. During chronic infection, plasma IL-10 and transcriptomic signatures of IL-10 signaling were correlated with the cell-associated SIV-DNA content within LN CD4 + memory subsets, including TFH, and predicted the frequency of CD4 + TFH and their cell-associated SIV-DNA content during ART, respectively. In ART-treated RMs, cells harboring SIV-DNA by DNAscope were preferentially found in the LN B-cell follicle in proximity to IL-10. Finally, we demonstrated that the in vivo neutralization of soluble IL-10 in ART-treated, SIV-infected macaques reduced B cell follicle maintenance and by extension LN memory CD4 + T-cells, including TFH and those expressing PD-1 and CTLA-4. Thus, these data support a role for IL-10 in maintaining a pool of target cells in lymphoid tissue that serve as a niche for viral persistence. Targeting IL-10 signaling to impair CD4 + T-cell survival and improve antiviral immune responses may represent a novel approach to limit viral persistence in ART-suppressed people living with HIV.

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Section: Discussionsupporting

confidence: 58%

Interleukin-10 contributes to reservoir establishment and persistence in SIV-infected macaques treated with antiretroviral therapy

Harper¹,

Ribeiro²,

Chan³

et al. 2022

Journal of Clinical Investigation

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“…Hanna et al. showed that IL‐10R/STAT3 pathway correlated with the accumulation of a PD‐1 int CD8 + T‐cell subset, which plays an important role in tumor elimination, and the loss of IL‐10R/STAT3 signaling enhanced the accumulation of functionally impaired PD‐1 hi CD8 + T‐cells associated with the progression of tumors in a chronic lymphocytic leukemia model 149 . Taken together, constitutive activation of STAT3 regulates the adaptive immune response in the chronic inflammatory TME and mediates immunosuppression in cancers (Figure 5).…”

Section: Regulation Of Cancer Hallmarks By the Stat3 Pathwaymentioning

confidence: 99%

STAT3 pathway in cancers: Past, present, and future

Wang

Man

Huo

et al. 2022

MedComm

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Signal transducer and activator of transcription 3 (STAT3), a member of the STAT family, discovered in the cytoplasm of almost all types of mammalian cells, plays a significant role in biological functions. The duration of STAT3 activation in normal tissues is a transient event and is strictly regulated. However, in cancer tissues, STAT3 is activated in an aberrant manner and is induced by certain cytokines. The continuous activation of STAT3 regulates the expression of downstream proteins associated with the formation, progression, and metastasis of cancers. Thus, elucidating the mechanisms of STAT3 regulation and designing inhibitors targeting the STAT3 pathway are considered promising strategies for cancer treatment. This review aims to introduce the history, research advances, and prospects concerning the STAT3 pathway in cancer. We review the mechanisms of STAT3 pathway regulation and the consequent cancer hallmarks associated with tumor biology that are induced by the STAT3 pathway. Moreover, we summarize the emerging development of inhibitors that target the STAT3 pathway and novel drug delivery systems for delivering these inhibitors. The barriers against targeting the STAT3 pathway, the focus of future research on promising targets in the STAT3 pathway, and our perspective on the overall utility of STAT3 pathway inhibitors in cancer treatment are also discussed.

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“…TGFβ signaling plays a major role in shaping the immunosuppressive tumor microenvironment [ 80 , 81 ]. Through transduction of IL10-induced signaling, IL10RB (IL10 receptor subunit beta) contributes to the immunosuppressive tumor microenvironment [ 82 , 83 ]. Consistent with this knowledge, BIRC5, MXD3, and RECQL4 expressions positively correlate with IL10RB expression ( Figure 8 ).…”

Section: Resultsmentioning

confidence: 99%

Prediction of Adrenocortical Carcinoma Relapse and Prognosis with a Set of Novel Multigene Panels

Lin

et al. 2022

Cancers

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Effective assessment of adrenocortical carcinoma (ACC) prognosis is critical in patient management. We report four novel and robust prognostic multigene panels. Sig27var25, SigIQvar8, SigCmbnvar5, and SigCmbn_B predict ACC relapse at area under the curve (AUC) of 0.89, 0.79, 0.78, and 0.80, respectively, and fatality at AUC of 0.91, 0.88, 0.85, and 0.87, respectively. Among their 33 component genes, 31 are novel. They could be differentially expressed in ACCs from normal tissues, tumors with different severity (stages and lymph node metastasis), ACCs with TP53 mutations, and tumors with differentially expressed immune checkpoints (CTLA4, PD1, TGFBR1, and others). All panels correlate with reductions of ACC-associated CD8+ and/or NK cells. Furthermore, we provide the first evidence for the association of mesenchymal stem cells (MSCs) with ACC relapse (p = 2 × 10−6) and prognosis (p = 2 × 10−8). Sig27var25, SigIQvar8, SigCmbnvar5, and SigCmbn_B correlate with MSC (spearman r ≥ 0.53, p ≤ 1.38 × 10−5). Sig27var25 and SigIQvar8 were derived from a prostate cancer (PC) and clear cell renal cell carcinoma (ccRCC) multigene signature, respectively; SigCmbnvar5 and SigCmbn_B are combinations of both panels, revealing close relationships of ACC with PC and ccRCC. The origin of these four panels from PC and ccRCC favors their prognostic potential towards ACC.

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Interleukin-10 receptor signaling promotes the maintenance of a PD-1int TCF-1+ CD8+ T cell population that sustains anti-tumor immunity

Cited by 73 publications

References 113 publications

Interleukin-10 contributes to reservoir establishment and persistence in SIV-infected macaques treated with antiretroviral therapy

Interleukin-10 contributes to reservoir establishment and persistence in SIV-infected macaques treated with antiretroviral therapy

STAT3 pathway in cancers: Past, present, and future

Prediction of Adrenocortical Carcinoma Relapse and Prognosis with a Set of Novel Multigene Panels

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