Introduction: KLRG1 is a lymphocyte co-inhibitory, or immune checkpoint, receptor expressed predominantly on late-differentiated effector and effector memory CD8+ T and NK cells.

Methods: We studied KLRG1 expression in human blood and tumor samples from available genomic datasets.

Results: KLRG1 is differentially expressed from CTLA-4 and PD-1, with predominant expression on cytotoxic CD8 T and NK cells over CD4 T cells. Within the CD8+ T cell population, KLRG1 expression, unlike CTLA-4 and PD-1 expression, is linked to greater antigen-driven differentiation states, with increased expression on CD45RO+CCR7- T effector memory (TEM) and CD45RA+CCR7- T effector memory RA (TEMRA) cells compared to CD45RA+CCR7+ naïve T cells (TN) and CD45RO+CCR7+ central memory T cells (TCM). The cytotoxic potential of CD8+ T cells, as assessed by the presence of cytokine and cytotoxic molecules IFNg, TNFa, perforin and granzyme B, is aligned with KLRG1, but not CTLA-4 or PD-1, expression. In single cell RNAseq analyses, KLRG1+ TILS accounted for 16-48% of CD8+ TILS, a frequency similar to that of PD-1+ TILS, in renal cell carcinoma, hepatocellular carcinoma, melanoma, ovarian cancer, HNSCC, and astrocytoma. KLRG1 expression was numerically increased post-treatment in 20/21 (95%) of datasets, statistically significant in 10/21 (48%), in response to a range of treatments including radiotherapy, chemotherapy, endocrine therapy, and immunotherapies (including ipilimumab, nivolumab, and pidilizumab), over periods of time ranging from 1-25 weeks.

Conclusions: In human blood and tumor samples, KLRG1 expression is aligned with cytotoxic T and NK cell differentiation, and upregulated in human tumor samples after a variety of therapies, potentially contributing to adaptive resistance. The upregulation of KLRG1 could contribute to limited efficacy and adaptive resistance that develops with current immunotherapies, and suggests KLRG1 blockade may work efficaciously, including as a neo-adjuvant therapy.

Citation Format: Steven A. Greenberg, Evan Thompson, Stefano V. Gulla. Differential expression of T cell co-inhibitory receptors: KLRG1 alignment with cytotoxicity and adaptive resistance mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3227.