NKG2C/tumor cell expression enhances immunotherapeutic efficacy against glioblastoma.

in Journal for immunotherapy of cancer by Olaya de Dios, M Angeles Ramírez-González, Irene Gómez-Soria, Berta Segura-Collar, Juliana Manosalva, Diego Megías, Carlos E De Andrea, Leticia Fernández-Rubio, Aurelio Hernández-Laín, Juan M Sepúlveda-Sánchez, Maria E Rodriguez-Ruiz, Ángel Pérez-Núñez, Derek A Wainwright, Ricardo Gargini, Pilar Sánchez-Gómez

TLDR

  • This study explored the role of neoplastic NKG2C expression in shaping the immune profile of glioblastoma (GBM) and found that it is a predictive biomarker for positive responses to immune checkpoint inhibitor treatment.
  • The study suggests that neoplastic NKG2C expression on tumor cells is associated with a more favorable immune profile, characterized by reduced myeloid-derived suppressor cells and increased tumor-resident lymphocytes.

Abstract

Activating 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. We performed a transcriptomic analysis of several NK receptors with a focus on the activating receptor encoded byNKG2C, 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. We 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. Neoplasticexpression 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 NKG2C-expressing tumors both in mouse models and patients with GBM whereas the expression of inhibitory NK receptors showed an inverse association. This study explored the role of neoplastic NKG2C/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.

Overview

  • The study aimed to explore the expression of activating and inhibitory receptors of natural killer cells in glioblastoma (GBM) to gain insights into their role in the intratumoral microenvironment.
  • The researchers analyzed bulk and single-cell RNA sequencing data sets to characterize the expression of various NK receptors, with a focus on NKG2C.
  • The study also investigated the effects of KLRC2-overexpressing GL261 cells in mice treated with or without programmed cell death protein-1 (PD-1) monoclonal antibody (mAb) and analyzed samples from two clinical trials evaluating PD-1 mAb effects in patients with GBM.

Comparative Analysis & Findings

  • The expression of inhibitory NK receptors was significantly higher on GBM-infiltrating NK and T cells, while KLRC2 was strongly expressed on tumor cells, mainly at the infiltrative margin.
  • Neoplastic KLRC2 expression was associated with a reduction in myeloid-derived suppressor cells and a higher level of tumor-resident lymphocytes.
  • The expression of NKG2C showed an inverse association with inhibitory NK receptors, and a stronger antitumor activity was observed in NKG2C-expressing tumors after PD-1 mAb treatment in both mouse models and patients with GBM.

Implications and Future Directions

  • The study suggests that neoplastic NKG2C expression 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, which could lead to the development of personalized therapeutic strategies for GBM patients.
  • Understanding the mechanisms underlying the immune evasion strategies of GBM tumors and identifying potential biomarkers could lead to the development of more effective treatments for this aggressive disease.
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