Stem-like CD4 T differentiation controls CD8 T cell immunity or tolerance in cancer

Abstract In this work we wanted to understand how CD4 T cell differentiation shapes the CD8 T cell response in cancer. We identified a population of tumor specific CD4 T cells that maintain an activated, undifferentiated phenotype throughout the cancer response. These CD4 T cells were the dominant population within tumor draining lymph nodes (TDLNs), characterized by high expression of TCF1 and little to no expression of other lineage defining transcription factors. Tumor specific TCF1+ CD4s exhibited functional stem-like properties, as they self-renewed and differentiated almost exclusively into Tregs in tumor bearing mice. These cells, however, were not limited to Treg differentiation, as sorted TCF1+ CD4s from a 5-week tumor response expanded and gave rise to TH1 and TFH effectors in response to LCMV Armstrong infection. Interestingly, we also found a similar population of activated PD1+ TCF1+ CD4s with stem-like capabilities infiltrating various human tumors, indicating this phenotype of CD4s is comparable in human cancer and mouse models. Importantly, the choice of lineage differentiation of TCF1+ CD4s regulated the quality of the CD8 T cell anti-tumor response. When Tregs were selectively depleted, TCF1+ CD4s differentiated into TH1s, which enhanced tumor specific CD8 T cell effector differentiation in both tumor and TDLNs, resulting in reduced tumor burden. Using a bone marrow chimeric CRISPR-Cas9 approach, we found that IFNg from TH1s was intrinsically required for CD8 stem to effector differentiation within TDLNs, promoting an improved anti-tumor response. Overall, this work shows that CD4 differentiation dictates tolerance or immunity in cancer by regulating the phenotype and magnitude of the effector CD8 T cell response.