Dual PD-1 and CTLA-4 Checkpoint Blockade Promotes Antitumor Immune Responses through CD4+Foxp3- Cell-Mediated Modulation of CD103+ Dendritic Cells

Immunotherapy is widely accepted as a powerful new treatment modality for the treatment of cancer. The most successful form of immunotherapy to date has been the blockade of the immune checkpoints PD-1 and CTLA-4. Combining inhibitors of both PD-1 and CTLA-4 increases the proportion of patients who respond to immunotherapy. However, most patients still do not respond to checkpoint inhibitors, and prognostic biomarkers are currently lacking. Therefore, a better understanding of the mechanism by which these checkpoint inhibitors enhance antitumor immune responses is required to more accurately predict which patients are likely to respond and further enhance this treatment modality. Our current study of two mouse tumor models revealed that CD4 thorn Foxp3(-) cells activated by dual PD-1/CTLA-4 blockade modulated the myeloid compartment, including activation of conventional CD103(+) dendritic cells (DC) and expansion of a myeloid subset that produces TNF alpha and iNOS (TIP-DCs). CD4(+)Foxp3(-) T cell-mediated activation of CD103(+) DCs resulted in enhanced IL12 production by these cells and IL12 enhanced the therapeutic effect of dual PD-1/CTLA-4 blockade. Given the importance of these myeloid subsets in the antitumor immune response, our data point to a previously underappreciated role of CD4(+)Foxp3(-) cells in modulating this arm of the antitumor immune response. (C) 2018 AACR.