Abstract
Abstract Immune checkpoint blockade (ICB) strategies have transformed immunotherapy with demonstrated efficacy including in melanoma. Nonetheless, most tumors do not respond to approved ICB agents. PDL2 is a relatively understudied immune checkpoint molecule that binds PD1 with higher affinity than PDL1, and also binds RGMb. We found that αPDL2 effectively treats subcutaneous B16 and Nras-mutated melanomas in aged but not young mice. αPDL2 efficacy in aged B16 requires host IL17 which induces IFNγ and is mediated by both γδ and CD8+ T cells. IL17 increased CXCR3+IFNγ+ immune cells, also supporting improved trafficking as a mechanism. αPDL2 augments B16-infiltrating γδ T cell numbers in aged mice, which boost tumor-infiltrating CD8+ T cell functions (e.g., IFNγ[TC1] ) but not numbers. CD8+ T cells did not appear to improve δγ T cell functions or numbers. αPDL2 also increased tumor infiltrating NK cells, CD4+ T cells, and dendritic cells that can mediate anti-tumor immunity. αPDL2 effectively treats heterotopic subcutaneous MB49 bladder cancer in young and aged mice showing effects are not restricted to only aged. Furthermore, lack of tumor PDL2 expression did not alter αPDL2 efficacy observed. PDL2 is thus a viable ICB target for treatment of cancer in select patient populations, including the aged.
Published Version
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