Abstract
Low or absent expression of major histocompatibility complex (MHC) on tumor cells is a presumed mechanism of resistance to immunotherapy, but evidence for this has largely been indirect. Likewise, whether immunotherapy can be effective without tumor MHC expression is also poorly understood. Using genetically-engineered mouse tumor cells expressing the model neoantigen ovalbumin (OVA), we found that MHC class I-deficient tumor cells, but not MHC class I-sufficient tumor cells, grew progressively when injected subcutaneously into syngeneic C57BL/6 mice. However, combination immunotherapy using agonistic anti-CD40 and dual immune checkpoint blockade (ICB) (anti-PD1 and anti-CTLA-4) was equally effective against tumors that did not express the MHC class I H-2Kb allele, MHC class II, or IFN-γ receptor across multiple pancreatic tumor lines (regardless of OVA). Moreover, CD4+ T cells, but not CD8+ T cells or perforin, were necessary to mediate immunotherapeutic responses. We excluded a role for CD4+ T cell-instructed macrophage-mediated tumor cell death but observed reprogramming of MHC class II-expressing stromal cells within the tumor after anti-CD40/ICB treatment. These data indicate that cancer immune surveillance by T cells does not absolutely require tumor-expressed MHC class I nor CD8+ T cells but instead can facilitate a clinically relevant remodeling of endothelial cells, further underscoring tumor-extrinsic roles for CD4+ T cells as mediators of tumor rejection and durable immune memory.