NKG2D controls natural reactivity of Vγ9Vδ2 T lymphocytes against mesenchymal glioblastoma cells Vγ9Vδ2 T lymphocytes react against mesenchymal glioblastoma

• Published in: Clinical cancer research
• Main Authors: Chauvin, Cynthia, Joalland, Noémie, Perroteau, Jeanne, Jarry, Ulrich, Lafrance, Laura, Willem, Catherine, Retiere, Christelle, Oliver, Lisa M, Gratas, Catherine, Gautreau-Rolland, Laetitia, Saulquin, Xavier, Vallette, François M, Vié, Henri, Scotet, Emmanuel, Pecqueur, Claire
• Format: Journal Article
• Language: English
• Published: American Association for Cancer Research 10.09.2019
• Subjects: Cancer; Life Sciences; Human; glioblastoma; immunotherapy; molecular subtype; Vγ9Vδ2 T lymphocytes
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-19-0375

PURPOSE:Cellular immunotherapies are currently being explored to eliminate highly invasive and chemoradioresistant glioblastoma (GBM) cells involved in rapid relapse. We recently showed that concomitant stereotactic injections of non-alloreactive allogeneic Vγ9Vδ2 T lymphocytes eradicate zoledronate-primed human GBM cells. In the present study, we investigated the spontaneous reactivity of allogeneic human Vγ9Vδ2 T lymphocytes toward primary human GBM cells, in vitro and in vivo, in absence of any prior sensitization.EXPERIMENTAL DESIGN:Through functional and trancriptomic analyses, we extensively characterized the immunoreactivity of human Vγ9Vδ2 T lymphocytes against various primary GBM cultures directly derived from patient tumors.RESULTS:We evidence that GBM cells displaying a mesenchymal subtype signature are spontaneously eliminated by allogeneic human Vγ9Vδ2 T lymphocytes, a reactivity process being mediated by γδ TCR and tightly regulated by cellular stress-associated NKG2D pathway. This led to the identification of highly-reactive Vγ9Vδ2 T lymphocyte populations, independently of a specific TCR repertoire signature. Moreover, we finally provide evidence of immunotherapeutic efficacy in vivo, in absence of any prior tumor cell sensitization.CONCLUSIONS:By identifying pathways implicated in the selective natural recognition of mesenchymal GBM cell subtypes, accounting for 30% of primary diagnosed and 60% of recurrent GBM, our results pave the way for novel targeted cellular immunotherapies.Copyright ©2019, American Association for Cancer Research.