Abstract
Recently, combination checkpoint therapy of cancer has been recognized as producing additive as opposed to synergistic benefit due in part to positively correlated effects. The potential for uncorrelated or negatively correlated therapies to produce true synergistic benefits has been noted. Whereas the inhibitory receptors PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT have been collectively characterized as exhaustion receptors, another inhibitory receptor KLRG1 was historically characterized as a senescent receptor and received relatively little attention as a potential checkpoint inhibitor target. The anti-tumor effects of KLRG1 blockade has relatively recently been demonstrated in preclinical in vivo studies. Here, expression of the inhibitory receptors PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, and KLRG1 was studied in publicly available gene expression datasets. Bulk RNA microarray and RNAseq, and single cell RNAseq data from healthy blood and tumor tissue samples were analyzed for Pearson correlation. CD8 T cell differentiation of memory T cells from the TEM to TEMRA states is characterized by PD-1/KLRG1 anti-correlation, with decreased PD-1 expression but increased KLRG1 expression. Single cell RNAseq analysis of tumor infiltrating CD8 T cells shows positive correlation of CTLA-4, TIM-3, LAG-3, TIGIT, GITR, 4-1BB, and OX40 with PD-1 but negative correlation of KLRG1 with PD-1. The anti-correlation of PD-1 and KLRG1 expression in human tumor infiltrating CD8 T cells suggests the potential for combination therapy supra-additive benefits of anti-PD-1 and anti-KLRG1 therapies.