Recently, combination checkpoint therapy of cancer has been recognized as producing additive as opposed to synergistic benefit due to in part to positively correlated effects. The potential for uncorrelated or negatively correlated therapies to produce true synergistic benefits has been noted. Whereas the co-inhibitory receptors PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT have been collectively characterized as exhaustion receptors, another co-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 co-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, and TIGIT 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.

SG has completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declares: SG is a founder and consultant to Abcuro, Inc. and inventor of intellectual property pertaining to KLRG1 targeting, owned and managed by the Brigham and Womens Hospital. There are no other relationships or activities that could appear to have influenced the submitted work.

This study did not receive any funding

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Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The source data were openly available before the initiation of the study and can be located in the GEO database under accession numbers GSE107011, GSE72046, GSE98638, GSE103322, GSE89567, GSE102575, GSE108989, GSE99531, and GSE99254; and abstracted from publications with PubMedIDs 22347406 and 29892065.

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All data used are publicly available in online databases and publications as described in Methods.