4.8 Article

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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IMMUNITY
卷 56, 期 1, 页码 162-+

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CELL PRESS
DOI: 10.1016/j.immuni.2022.12.006

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PD1-IL2v is an engineered immunocytokine that delivers IL2v precisely to PD-1+ T cells in the tumor microenvironment, resulting in infiltration by stem-like CD8+ T cells and enhanced tumor regression and survival in mice. Combining PD1-IL2v with anti-PD-L1 improves therapeutic efficacy by reprogramming tumor-associated macrophages and enhancing T cell receptor immune repertoire diversity. These findings support the clinical evaluation of PD1-IL2v and anti-PD-L1 combination therapy in immunotherapy-resistant tumors infiltrated with PD-1+ stem-like T cells.
Immunotherapies have shown remarkable, albeit tumor-selective, therapeutic benefits in the clinic. Most pa-tients 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 reprogram-ming 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.

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