Targeted Alpha Particle Therapy Remodels the Tumor Microenvironment and Improves Efficacy of Immunotherapy.

Autor:	Perrin J; CRCINA, INSERM, CNRS, Université de Nantes, Université d'Angers, Nantes, France., Capitao M; CRCINA, INSERM, CNRS, Université de Nantes, Université d'Angers, Nantes, France., Allard M; CRCINA, INSERM, CNRS, Université de Nantes, Université d'Angers, Nantes, France., Chouin N; CRCINA, INSERM, CNRS, ONIRIS, Université de Nantes, Université d'Angers, Nantes, France., Gouard S; CRCINA, INSERM, CNRS, Université de Nantes, Université d'Angers, Nantes, France., Marionneau-Lambot S; CRCINA, INSERM, CNRS, Université de Nantes, Université d'Angers, Nantes, France., Louvet C; Centre de Recherche en Transplantation et Immunologie, INSERM, Université de Nantes, Nantes, France., Donnadieu E; INSERM, U1016, Institut Cochin, CNRS, UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France., Bruchertseifer F; European Commission, Joint Research Centre (JRC), Karlsruhe, Germany., Morgenstern A; European Commission, Joint Research Centre (JRC), Karlsruhe, Germany., Chérel M; CRCINA, INSERM, CNRS, Université de Nantes, Université d'Angers, Nantes, France; Nuclear Medicine Unit, ICO Cancer Center Gauducheau, Saint Herblain, France., Gaschet J; CRCINA, INSERM, CNRS, Université de Nantes, Université d'Angers, Nantes, France., Guilloux Y; CRCINA, INSERM, CNRS, Université de Nantes, Université d'Angers, Nantes, France. Electronic address: yannick.guilloux@univ-nantes.fr.
Jazyk:	angličtina
Zdroj:	International journal of radiation oncology, biology, physics [Int J Radiat Oncol Biol Phys] 2022 Mar 01; Vol. 112 (3), pp. 790-801. Date of Electronic Publication: 2021 Oct 23.
DOI:	10.1016/j.ijrobp.2021.10.013
Abstrakt:	Purpose: The tumor microenvironment (TME) can severely impair immunotherapy efficacy by repressing the immune system. In a multiple myeloma (MM) murine model, we investigated the impact of targeted alpha particle therapy (TAT) on the immune TME. TAT was combined with an adoptive cell transfer of CD8 T cells (ACT), and the mechanisms of action of this combination were assessed at the tumor site. Methods and Materials: This combination treatment was conducted in a syngeneic MM murine model grafted subcutaneously. TAT was delivered by intravenous injection of a bismuth-213 radiolabeled anti-CD138 antibody. To strengthen antitumor immune response, TAT was combined with an ACT of tumor-specific CD8+ OT-1 T-cells. The tumors were collected and the immune TME analyzed by flow cytometry, immunohistochemistry, and ex vivo T-cell motility assay on tumor slices. The chemokine and cytokine productions were also assessed by quantitative reverse transcription polymerase chain reaction. Results: Tumor-specific CD8+ OT-1 T cells infiltrated the tumors after ACT. However, only treatment with TAT resulted in regulatory CD4 T-cell drop and transient increased production of interleukin-2, CCL-5, and interferon-γ within the tumor. Moreover, OT-1 T-cell recruitment and motility were increased on tumor slices from TAT-treated mice, as observed via ex vivo time lapse, contributing to a more homogeneous distribution of OT-1 T cells in the tumor. Subsequently, the tumor cells increased PD-L1 expression, antitumor cytokine production decreased, and OT-1 T-cells overexpressed exhaustion markers, suggesting an exhaustion of the immune response. Conclusion: Combining TAT and ACT seems to transiently remodel the cold TME, improving ACT efficiency. The immune response then leads to the establishment of other tumor cell resistance mechanisms. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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