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

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 was assessed at the tumor site. This combination treatment was conducted in a syngeneic MM murine model grafted subcutaneously. TAT was delivered by i.v. injection of a 213-bismuth radiolabelled anti-CD138 antibody. To strengthen anti-tumor response, TAT was combined with an ACT of tumor specific OT-1 T-cells. This therapeutic combination resulted in tumor growth delay. The tumors were collected and the immune TME analyzed by flow cytometry, immunohistochemistry and ex vivo motility assay on tumor slices. The chemokine and cytokine productions were also assessed by RT-qPCR. OT-1 T-cells infiltrated the tumors after ACT. However only when combined with TAT, it resulted in regulatory CD4 T-cell drop and production of IL-2, CCL-5 and IFN within the tumor. Moreover, OT-1 T-cell motility was increased on TAT treated tumor slices 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, implying an exhaustion of the immune response. Combining TAT and ACT seems to turn this “cold” tumor model into a “hot” one, leading to tumor cell resistance mechanisms.

PERRIN Justine;  CAPITAO Marisa;  ALLARD M;  CHOUIN N;  GOUARD S.;  MARIONNEAU-LAMBOT S;  LOUVET Cedric;  DONNADIEU E;  BRUCHERTSEIFER Frank;  MORGENSTERN Alfred;  CHEREL M.;  GASCHET J;  GUILLOUX Yannick; 

2022-03-28

ELSEVIER SCIENCE INC

JRC125992

0360-3016 (online),   

www.sciencedirect.com/science/article/pii/S0360301621029199,    https://publications.jrc.ec.europa.eu/repository/handle/JRC125992,   

10.1016/j.ijrobp.2021.10.013 (online),