NKG2C/ KLRC2 tumor cell expression enhances immunotherapeutic efficacy against glioblastoma.

Autor:	de Dios O; Neurooncology Unit, Chronic Disease Deparment (UFIEC), Instituto de Salud Carlos III, Majadahonda, Madrid, Spain., Ramírez-González MA; Neurooncology Unit, Chronic Disease Deparment (UFIEC), Instituto de Salud Carlos III, Majadahonda, Madrid, Spain., Gómez-Soria I; Neurooncology Unit, Chronic Disease Deparment (UFIEC), Instituto de Salud Carlos III, Majadahonda, Madrid, Spain., Segura-Collar B; Neurooncology Unit, Instituto de Investigaciones Biomédicas I+12, Hospital Universitario 12 de Octubre, Madrid, Spain.; Department of Anatomical Pathology, Hospital Universitario 12 de Octubre, Madrid, Spain., Manosalva J; Advanced Microscopy Unit, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain., Megías D; Advanced Microscopy Unit, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain., De Andrea CE; Department of Anatomy, Physiology and Pathology, Universidad de Navarra, Pamplona, Navarra, Spain.; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain., Fernández-Rubio L; Division of Immunology and Immunotherapy, Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), Pamplona, Navarra, Spain., Hernández-Laín A; Neurooncology Unit, Instituto de Investigaciones Biomédicas I+12, Hospital Universitario 12 de Octubre, Madrid, Spain.; Department of Neuropathology, Hospital Universitario 12 de Octubre, Madrid, Spain., Sepúlveda-Sánchez JM; Neurooncology Unit, Instituto de Investigaciones Biomédicas I+12, Hospital Universitario 12 de Octubre, Madrid, Spain.; Hospital HM Sanchinarro, Centro Integral Oncologico Clara Campal, Madrid, Spain., Rodriguez-Ruiz ME; Division of Immunology and Immunotherapy, Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), Pamplona, Navarra, Spain.; Department of Radiation Oncology, Clinica Universidad de Navarra, Pamplona, Navarra, Spain., Pérez-Núñez Á; Department of Neurosurgery, Hospital Universitario 12 de Octubre, Madrid, Spain.; Department of Surgery, Universidad Complutense de Madrid, Facultad de Medicina, Madrid, Spain., Wainwright DA; Department of Neurological Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois, USA.; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois, USA., Gargini R; Neurooncology Unit, Instituto de Investigaciones Biomédicas I+12, Hospital Universitario 12 de Octubre, Madrid, Spain ricgargini.imas12@h12o.es psanchezg@isciii.es.; Department of Anatomical Pathology, Hospital Universitario 12 de Octubre, Madrid, Spain., Sánchez-Gómez P; Neurooncology Unit, Chronic Disease Deparment (UFIEC), Instituto de Salud Carlos III, Majadahonda, Madrid, Spain ricgargini.imas12@h12o.es psanchezg@isciii.es.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2024 Aug 30; Vol. 12 (8). Date of Electronic Publication: 2024 Aug 30.
DOI:	10.1136/jitc-2024-009210
Abstrakt:	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 NKG2C high -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. Competing Interests: Competing interests: MER-R reports personal fees from BMS and grants from Highlight-Therapeutics and Roche outside the submitted work. She also has received speaker’s bureau honoraria from BMS and ROCHE. The rest of the authors declare that they have no competing interests. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu