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

Abstract

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.