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

Cynthia Chauvin 1, 2 Noémie Joalland 3, 2 Jeanne Perroteau 3, 2 Ulrich Jarry 3, 2 Laura Lafrance 3, 2 Catherine Willem 3, 4 Christelle Retiere 3 Lisa Oliver 1 Catherine Gratas 5 Laetitia Gautreau-Rolland 3, 2 Xavier Saulquin 3, 2 François Vallette 1, 2, 6 Henri Vié 3, 2 Emmanuel Scotet 3, 2 Claire Pecqueur 5, 2, *
* Corresponding author
1 CRCINA - Département ONCO - Equipe 9 - Apoptosis and tumor progression -ATP
CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers
2 LabEX IGO Immunothérapie Grand Ouest
3 CRCINA - Département INCIT - Equipe 1 - Immunobiology of Human αβ and γδ T cells and Immunotherapeutic Applications
CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers
4 Etablissement Français du Sang [Nantes]
5 CRCINA - Département ONCO - Equipe 14 - Endothelium radiobiology and targeting
CRCINA - Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers
6 Institut de Cancérologie de l'Ouest René-Gauducheau [Saint-Herblain]
Abstract : 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.
Keywords : Human glioblastoma immunotherapy Vγ9Vδ2 T lymphocytes molecular subtype
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Cynthia Chauvin, Noémie Joalland, Jeanne Perroteau, Ulrich Jarry, Laura Lafrance, et al.. NKG2D controls natural reactivity of Vγ9Vδ2 T lymphocytes against mesenchymal glioblastoma cells: Vγ9Vδ2 T lymphocytes react against mesenchymal glioblastoma. Clinical Cancer Research, American Association for Cancer Research, In press, clincanres.0375.2019 (Epub ahead of print). ⟨10.1158/1078-0432.CCR-19-0375⟩. ⟨inserm-02316604⟩

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