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NKG2C/KLRC2 tumor cell expression enhances immunotherapeutic efficacy against glioblastoma
Olaya de Dios1, M Angeles Ramírez-González1, Irene Gómez-Soria1
1Neurooncology Unit, Chronic Disease Deparment (UFIEC), Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.
Background:
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.
Methods:
We 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.
Results:
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. 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.
Conclusions:
This 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.
Insights
Neoplastic NKG2C/KLRC2 expression in glioblastoma (GBM) correlates with reduced immunosuppression and predicts response to PD-1 blockade. This highlights NKG2C as a potential biomarker for immunotherapy in GBM patients.
Area of Science:
- Immunology
- Oncology
- Neuro-oncology
Background:
- Natural killer (NK) cell receptors, including activating and inhibitory types (e.g., NKp, NKG2, CLEC), are crucial in the tumor microenvironment of cold tumors like glioblastoma (GBM).
- Understanding NK receptor expression in GBM is vital for exploring their role in modulating the tumor immune landscape.
Purpose of the Study:
- To characterize the expression of NK receptors in GBM.
- To investigate the role of neoplastic KLRC2 (encoding NKG2C) in GBM's immune profile.
- To evaluate NKG2C as a predictive biomarker for response to PD-1 blockade in GBM.
Main Methods:
- Transcriptomic analysis of NK receptors, focusing on KLRC2/NKG2C, in bulk and single-cell RNA sequencing GBM datasets.
- In vivo studies using GL261 cells overexpressing KLRC2 in mice treated with anti-PD-1 monoclonal antibody (mAb).
- Analysis of clinical trial samples from GBM patients treated with anti-PD-1 mAb to assess NKG2C as a response biomarker.
Main Results:
- Significant expression of inhibitory NK receptors on GBM-infiltrating immune cells, contrasting with strong KLRC2 expression on tumor cells, particularly at the invasive margin.
- Neoplastic KLRC2 expression correlated with decreased myeloid-derived suppressor cells and increased tumor-resident lymphocytes.
- Tumors with high NKG2C expression demonstrated enhanced antitumor activity following PD-1 mAb treatment in both murine models and human GBM patients; inhibitory NK receptor expression showed an inverse correlation.
Conclusions:
- Neoplastic NKG2C/KLRC2 expression influences GBM's immune profile and serves as a predictive biomarker for favorable responses to immune checkpoint inhibitor therapy.
- NKG2C is a promising biomarker for predicting immunotherapy response in glioblastoma patients.
- Further validation in prospective clinical trials is warranted.
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