IFN-γ- and IL-17-producing CD8 + T (Tc17-1) cells in combination with poly-ICLC and peptide vaccine exhibit antiglioma activity.

Autor:	Ohkuri T; Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.; Brain Tumor Program, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, USA., Kosaka A; Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.; Brain Tumor Program, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, USA., Ikeura M; Brain Tumor Program, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, USA., Salazar AM; Oncovir, Inc, Washington, District of Columbia, USA., Okada H; Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA hideho.okada@ucsf.edu.; Brain Tumor Program, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Pittsburgh, PA, USA.; Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2021 Jun; Vol. 9 (6).
DOI:	10.1136/jitc-2021-002426
Abstrakt:	Background: While adoptive transfer of T-cells has been a major medical breakthrough for patients with B cell malignancies, the development of safe and effective T-cell-based immunotherapy for central nervous system (CNS) tumors, such as glioblastoma (GBM), still needs to overcome multiple challenges, including effective homing and persistence of T-cells. Based on previous observations that interleukin (IL)-17-producing T-cells can traffic to the CNS in autoimmune conditions, we evaluated CD8 + T-cells that produce IL-17 and interferon-γ (IFN-γ) (Tc17-1) cells in a preclinical GBM model. Methods: We differentiated Pmel-1 CD8 + T-cells into Tc17-1 cells and compared their phenotypic and functional characteristics with those of IFN-γ-producing CD8 + T (Tc1) and IL-17-producing CD8 + T (Tc17) cells. We also evaluated the therapeutic efficacy, persistence, and tumor-homing of Tc17-1 cells in comparison to Tc1 cells using a mouse GL261 glioma model. Results: In vitro, Tc17-1 cells demonstrated profiles of both Tc1 and Tc17 cells, including production of both IFN-γ and IL-17, although Tc17-1 cells demonstrated lesser degrees of antigen-specific cytotoxic activity compared with Tc1 cells. In mice-bearing intracranial GL261-Quad tumor and treated with temozolomide, Tc1 cells, but not Tc17-1, showed a significant prolongation of survival. However, when the T-cell transfer was combined with poly-ICLC and Pmel-1 peptide vaccine, both Tc1 and Tc17-1 cells exhibited significantly prolonged survival associated with upregulation of very late activation antigen-4 on Tc17-1 cells in vivo. Glioma cells that recurred following the therapy lost the susceptibility to Pmel-1-derived cytotoxic T-cells, indicating that immuno-editing was a mechanism of the acquired resistance. Conclusions: Tc17-1 cells were equally effective as Tc1 cells when combined with poly-ICLC and peptide vaccine treatment. Competing Interests: Competing interests: AMS is Chairman, CEO, Scientific Director and cofounder of Oncovir. (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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