Complete genomic characterization of a new KLRC2 allele, NKG2C*03.
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ABSTRACT:
SUBMITTER: Asenjo J
PROVIDER: S-EPMC8451841 | biostudies-literature | 2021 Sep
REPOSITORIES: biostudies-literature
Publications
Complete genomic characterization of a new KLRC2 allele, NKG2C*03.
Asenjo Judit J Muntasell Aura A López-Botet Miguel M Moraru Manuela M Vilches Carlos C
HLA 20210226 3
The novel NKG2C*03 allele encodes a hybrid of the NKG2C*01 and NKG2C*02 primary structures. ...[more]
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Project description:BackgroundActivating and inhibitory receptors of natural killer (NK) cells such as NKp, NKG2, or CLEC are highly relevant to cold tumors including glioblastoma (GBM). Here, we aimed to characterize the expression of these receptors in GBM to gain insight into their potential role as modulators of the intratumoral microenvironment.MethodsWe performed a transcriptomic analysis of several NK receptors with a focus on the activating receptor encoded by KLRC2, NKG2C, among bulk and single-cell RNA sequencing GBM data sets. We also evaluated the effects of KLRC2-overexpressing GL261 cells in mice treated with or without programmed cell death protein-1 (PD-1) monoclonal antibody (mAb). Finally, we analyzed samples from two clinical trials evaluating PD-1 mAb effects in patients with GBM to determine the potential of NKG2C to serve as a biomarker of response.ResultsWe observed significant expression of several inhibitory NK receptors on GBM-infiltrating NK and T cells, which contrasts with the strong expression of KLRC2 on tumor cells, mainly at the infiltrative margin. Neoplastic KLRC2 expression was associated with a reduction in the number of myeloid-derived suppressor cells and with a higher level of tumor-resident lymphocytes. A stronger antitumor activity after PD-1 mAb treatment was observed in NKG2Chigh-expressing tumors both in mouse models and patients with GBM whereas the expression of inhibitory NK receptors showed an inverse association.ConclusionsThis study explored the role of neoplastic NKG2C/KLRC2 expression in shaping the immune profile of GBM and suggests that it is a predictive biomarker for positive responses to immune checkpoint inhibitor treatment in patients with GBM. Future studies could further validate this finding in prospective trials.
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