Bispecific PD1-IL2v and anti-PD-L1 break tumor immunity resistance by enhancing stem-like tumor-reactive CD8+ T cells and reprogramming macrophages.
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10 janvier 2023
- doi: 10.1016/j.immuni.2022.12.006
- issn: 1074-7613
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info:eu-repo/semantics/altIdentifier/doi/10.1016/j.immuni.2022.12.006
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info:eu-repo/semantics/altIdentifier/pmid/36630914
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info:eu-repo/semantics/altIdentifier/urn/urn:nbn:ch:serval-BIB_D37AF3A7C8082
info:eu-repo/semantics/openAccess , CC BY-NC-ND 4.0 , https://creativecommons.org/licenses/by-nc-nd/4.0/
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M. Tichet et al., « Bispecific PD1-IL2v and anti-PD-L1 break tumor immunity resistance by enhancing stem-like tumor-reactive CD8+ T cells and reprogramming macrophages. », Serveur académique Lausannois, ID : 10.1016/j.immuni.2022.12.006
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Immunotherapies have shown remarkable, albeit tumor-selective, therapeutic benefits in the clinic. Most patients respond transiently at best, highlighting the importance of understanding mechanisms underlying resistance. Herein, we evaluated the effects of the engineered immunocytokine PD1-IL2v in a mouse model of de novo pancreatic neuroendocrine cancer that is resistant to checkpoint and other immunotherapies. PD1-IL2v utilizes anti-PD-1 as a targeting moiety fused to an immuno-stimulatory IL-2 cytokine variant (IL2v) to precisely deliver IL2v to PD-1 + T cells in the tumor microenvironment. PD1-IL2v elicited substantial infiltration by stem-like CD8 + T cells, resulting in tumor regression and enhanced survival in mice. Combining anti-PD-L1 with PD1-IL2v sustained the response phase, improving therapeutic efficacy both by reprogramming immunosuppressive tumor-associated macrophages and enhancing T cell receptor (TCR) immune repertoire diversity. These data provide a rationale for clinical trials to evaluate the combination therapy of PD1-IL2v and anti-PD-L1, particularly in immunotherapy-resistant tumors infiltrated with PD-1 + stem-like T cells.