PD-L2 blockade alters myeloid cells and could promote innate behavior in T cells to treat melanoma in the aged host in mechanisms distinct from αPD1 2250522

Abstract Introduction Overall, immune checkpoint blockade (ICB) response remains low at ∼15%, indicating better treatment options are needed. ICB requires IFNγ for maximum efficacy but mechanisms for its elicitation are incompletely defined, and effects differ in young versus aged. Methods We published that aged mice but not young mice use IL17 to generate IFNγ with αPDL2 ICB. We hypothesized that IL17 induces innate-like IFNγ and that aged hosts were more susceptible to such behavior in adaptive cells. We used agonists for CD134 and CD137, αCTLA4, or cytokines (IL2+IL33) to elicit innate behavior in adaptive T cells in vitro and/or in vivo in young or aged immune cells. We generated scRNA-seq data from intra-tumoral immune cells in melanoma bearing aged-hosts and show αPDL2-driven alterations to melanoma infiltrating immune cells in the aged host, distinct from isotype or αPD1 treated hosts. Results In vitro, αCD134+αCD137 or IL2+IL33 elicited innate IFNγ and increased Eomes expression in CD4 and CD8 T cells as expected, and IL17 augmented the effect. Young mice with melanoma do not respond to αPDL2, but CD134 + CD137 agonists or αCTLA4 elicited αPD-L2 efficacy, with the former increasing CD8 T cell IFNγ and Eomes, consistent with augmented innate IFNγ from adaptive cells. In aged mice that respond to αPDL2 alone, scRNA-seq analysis showed αPD-L2 increases CD4 and γδ T cell abundance accompanied by a striking decrease in S100A9Hi cell abundance and other myeloid cell effects, distinct from αPD-1. Thus, myeloid cells could contribute to these effects. Conclusion PDL2 is a strong ICB target, distinct from PD-1 in important ways including myeloid cell effects and mechanisms of IFNγ induction unique from other ICB thus far, and αPDL2 could be used in rational combinations to overcome ICB resistance. Funding Source Gmelich chair and Guyre funds Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)