Progressive loss of differentiated effector CD8 T cells infiltrating melanoma (TUM7P.1021)

Abstract

Abstract CD8 tumor infiltrating lymphocytes (TIL) are critical for tumor control and their presence is a positive prognostic factor. Understanding CD8 TIL dysfunction is vital for developing cancer immunotherapies. Here, using a Granzyme B Cre ROSA YFP reporter system, we characterized the differentiation of CD8 T cells over the course of tumor growth using a murine melanoma model. At early stages of the CD8 T cell response (day 10 after tumor injection), the majority of the cells had differentiated to express Granzyme B (YFP+). However, over a period of four days, most of these effector cells were replaced by CD8+ T cells that had no evidence of effector differentiation. Concurrently, we found an increase in expression of the inhibitory receptor PD-1 in differentiated (YFP+) relative to non-differentiated (YFP-) CD8 TIL in late stage tumors. This suggests that there is both a loss of differentiated CD8 TIL and that the differentiated CD8 T cells that remain are more dysfunctional in late stage tumors. To provide insight into the cause and effect of this fluctuation in differentiation, we present data establishing the contribution of checkpoint inhibitory molecules and dendritic cell activation state in the loss of effector characteristics, and whether cytokine production and other effector activities correlate with the shift in effector differentiation status.