Tu147 - Regulatory T Cell Functional Dynamics During The Response To PD-1 Blockade

Checkpoint inhibitors have been a major breakthrough in cancer therapy, inducing durable remission in patients. Yet, roughly 2/3 of patients do not respond to treatment in melanoma, the solid tumor type with maximal efficacy. Positive clinical outcomes are associated with higher degrees of pre-existing inflammation in the tumor microenvironment, while non-responding tumors are “cold”. Regulatory T cells (T_reg) play a dominant role in tumor-induced immunosuppression. However, it is still unclear how their homeostasis differs in these different tumor microenvironments and how this impacts the outcome of checkpoint blockade. We hypothesize that checkpoint inhibitors dysregulate the homeostasis and the fate of T_reg cells, thus increasing anti-tumor responses.

Using various syngeneic mouse models of “cold” (D4M.3A) and “hot” (YUMMER1.7) melanoma and Foxp3-reporter strains, we mapped out local and systemic regulatory T cells dynamics throughout tumor growth and response to checkpoint blockade. Despite different potency, in both models anti-PD1 delayed tumor growth and increased local CD8 responses. However, this increased inflammation was associated with T_reg cells displaying reduced PD-1 expression and a more highly activated phenotype both in the tumor and systemically. Furthermore, we established that in a subset of high responders, tumor-infiltrating T_reg cells progressively acquire Th1-like characteristics, namely expression of T-bet and secretion of IFNγ. This phenotype was strongly correlated with both strong CD8 anti-tumor responses and reduced tumor volume. Nonetheless, T_reg cells isolated from these tumors highly suppress the proliferation of splenic T_resp cells in vitro. Thus, it remains to be determined which signals dampen their suppressive capacity in situ.