Tichet, MelanieWullschleger, StephanChryplewicz, AgnieszkaFournier, NadineMarcone, RachelKauzlaric, AnnamariaHomicsko, KrisztianDeak, Laura CodarriUmana, PabloKlein, ChristianHanahan, Douglas2023-05-082023-05-082023-05-082023-01-1010.1016/j.immuni.2022.12.006https://infoscience.epfl.ch/handle/20.500.14299/197503WOS:000963126500001Immunotherapies 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.ImmunologyImmunologycd8(+) t-cellsimmunotherapydifferentiationinterleukin-2normalizationmodulationexpressiontoleranceantigenpd-l1text::journal::journal article::research article