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IL10 and PD-1 Cooperate to Limit the Activity of Tumor-Specific CD8+ T Cells.

ABSTRACT: Immune checkpoint inhibitors show great promise as therapy for advanced melanoma, heightening the need to determine the most effective use of these agents. Here, we report that programmed death-1(high) (PD-1(high)) tumor antigen (TA)-specific CD8(+) T cells present at periphery and at tumor sites in patients with advanced melanoma upregulate IL10 receptor (IL10R) expression. Multiple subsets of peripheral blood mononucleocytes from melanoma patients produce IL10, which acts directly on IL10R(+) TA-specific CD8(+) T cells to limit their proliferation and survival. PD-1 blockade augments expression of IL10R by TA-specific CD8(+) T cells, thereby increasing their sensitivity to the immunosuppressive effects of endogenous IL10. Conversely, IL10 blockade strengthened the effects of PD-1 blockade in expanding TA-specific CD8(+) T cells and reinforcing their function. Collectively, our findings offer a rationale to block both IL10 and PD-1 to strengthen the counteraction of T-cell immunosuppression and to enhance the activity of TA-specific CD8(+) T cell in advanced melanoma patients.

SUBMITTER: Sun Z

PROVIDER: S-EPMC4401638 | biostudies-other | 2015 Apr

REPOSITORIES: biostudies-other

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IL10 and PD-1 Cooperate to Limit the Activity of Tumor-Specific CD8+ T Cells.

Sun Zhaojun Z Fourcade Julien J Pagliano Ornella O Chauvin Joe-Marc JM Sander Cindy C Kirkwood John M JM Zarour Hassane M HM

Cancer research 20150226 8

Immune checkpoint inhibitors show great promise as therapy for advanced melanoma, heightening the need to determine the most effective use of these agents. Here, we report that programmed death-1(high) (PD-1(high)) tumor antigen (TA)-specific CD8(+) T cells present at periphery and at tumor sites in patients with advanced melanoma upregulate IL10 receptor (IL10R) expression. Multiple subsets of peripheral blood mononucleocytes from melanoma patients produce IL10, which acts directly on IL10R(+) ...[more]

PMID: 25720800

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Project description:Coinhibitory PD-1/PD-L1 (B7-H1) interactions provide critical signals for the regulation of autoreactive T-cell responses. We established mouse models, expressing the costimulator molecule B7.1 (CD80) on pancreatic beta cells (RIP-B7.1 tg mice) or are deficient in coinhibitory PD-L1 or PD-1 molecules (PD-L1(-/-) and PD-1(-/-) mice), to study induction of preproinsulin (ppins)-specific CD8 T-cell responses and experimental autoimmune diabetes (EAD) by DNA-based immunization. RIP-B7.1 tg mice allowed us to identify two CD8 T-cell specificities: pCI/ppins DNA exclusively induced K(b)/A(12-21)-specific CD8 T-cells and EAD, whereas pCI/ppinsΔA(12-21) DNA (encoding ppins without the COOH-terminal A(12-21) epitope) elicited K(b)/B(22-29)-specific CD8 T-cells and EAD. Specific expression/processing of mutant ppinsΔA(12-21) (but not ppins) in non-beta cells, targeted by intramuscular DNA-injection, thus facilitated induction of K(b)/B(22-29)-specific CD8 T-cells. The A(12-21) epitope binds K(b) molecules with a very low avidity as compared with B(22-29). Interestingly, immunization of coinhibition-deficient PD-L1(-/-) or PD-1(-/-) mice with pCI/ppins induced K(b)/A(12-21)-monospecific CD8 T-cells and EAD but injections with pCI/ppinsΔA(12-21) did neither recruit K(b)/B(22-29)-specific CD8 T-cells into the pancreatic target tissue nor induce EAD. PpinsΔA(12-21)/(K(b)/B(22-29))-mediated EAD was efficiently restored in RIP-B7.1(+)/PD-L1(-/-) mice, differing from PD-L1(-/-) mice only in the tg B7.1 expression in beta cells. Alternatively, an ongoing beta cell destruction and tissue inflammation, initiated by ppins/(K(b)/A(12-21))-specific CD8 T-cells in pCI/ppins+pCI/ppinsΔA(12-21) co-immunized PD-L1(-/-) mice, facilitated the expansion of ppinsΔA(12-21)/(K(b)/B(22-29))-specific CD8 T-cells. CD8 T-cells specific for the high-affinity K(b)/B(22-29)- (but not the low-affinity K(b)/A(12-21))-epitope thus require stimulatory help from beta cells or inflamed islets to expand in PD-L1-deficient mice. The new PD-1/PD-L1 diabetes models may be valuable tools to study under well controlled experimental conditions distinct hierarchies of autoreactive CD8 T-cell responses, which trigger the initial steps of beta cell destruction or emerge during the pathogenic progression of EAD.

Dataset Information

IL10 and PD-1 Cooperate to Limit the Activity of Tumor-Specific CD8+ T Cells.

Publications

IL10 and PD-1 Cooperate to Limit the Activity of Tumor-Specific CD8+ T Cells.

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