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Journal Articles International Journal of Radiation Oncology, Biology, Physics Year : 2021

Targeted alpha particle therapy remodels the tumor microenvironment and improves efficacy of immunotherapy

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Abstract

Purpose : 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 : This combination treatment was conducted in a syngeneic MM murine model grafted subcutaneously. TAT was delivered by i.v. injection of a bismuth-213 radiolabelled anti-CD138 antibody. To strengthen anti-tumor 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 RT-qPCR. 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 IL-2, CCL-5 and IFNγ within the tumor. Moreover, OT-1 T-cell recruitment and motility were increased on tumor slices from TAT-treated mice as observed by 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, anti-tumor 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.
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Dates and versions

inserm-03403252 , version 1 (26-10-2021)

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Justine Perrin, M Capitao, M Allard, N Chouin, S Gouard, et al.. Targeted alpha particle therapy remodels the tumor microenvironment and improves efficacy of immunotherapy. International Journal of Radiation Oncology, Biology, Physics, 2021, Online ahead of print. ⟨10.1016/j.ijrobp.2021.10.013⟩. ⟨inserm-03403252⟩
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