PD1 Blockade of Tumor-primed CD4 T Cells Instigates Protective Immunity Against Tumor Rechallenge.

Abstract

Abstract Blockade of immune checkpoint PD1 in cancer patients results in remarkable therapeutic benefits. Revealing mechanisms underlying this revolutionary therapy is critical to identifying biomarkers for predicting responses to this treatment and developing novel PD1 blockade combined therapeutic regimens for broader clinical efficacy. Rejuvenation of preexisting intratumoral ‘exhausted’ T cells and recruitment of peripheral antitumor T cells into tumors have been suggested to explain how PD1 blockade works, but mechanisms of action of anti-PD1 therapy remain to be fully delineated. In a clinically relevant mouse model of spontaneous metastatic breast cancer 4T1.2-Neu, we show that effective and durable anti-PD1 therapy depends on systemic immunity, including type 1 conventional dendritic cells (cDC1: CD8α+/CD103+DC), B cells, CD4 and CD8 T cells. Increased circulating and/or tumor-infiltrating IL12+CD103+DC and IL2+CD4/CD8 T cells are associated with the response to anti-PD1 therapy. PD1 blockade results in tumor-primed CD44+IL2+CD4T cells in the periphery regardless of cDC1. In the breast cancer model with adoptive cell transfer (ACT), PD1 blockade-driven CD44+CD4+T cells infiltrate into tumors and ignite protective immunity against new tumors in an IL2-dependent and tumor-specific manner. In a distinct ACT model using enforced IL2-expressing melanoma antigen specific TRP1-transgenic (Tg) CD4 T cells, IL2+TRP1-Tg CD4 T cells control the growth of PD1-resistant endogenous BP or B16 melanoma. These data suggest the prominent role of PD1 blockade on the effectiveness of tumor-primed CD4T cells in tumor-specific immunity.