CD4+ T Cells Mediate MHC-Deficient Tumor Rejection and Endothelial Cell Reprogramming

Abstract Low or absent expression of 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, 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 (anti–PD-1 and anti–CTLA-4) was equally effective against tumors that did not express the MHC class I H-2Kb allele, MHC class II, or IFNγ receptor across multiple pancreatic tumor lines (regardless of ovalbumin). 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.