LAUSR

A considerable proportion of cancer patients are resistant or only partially responsive to immune checkpoint blockade immunotherapy. Tumor-Associated Macrophages (TAMs) infiltrating the tumor stroma suppress the adaptive immune responses and hence promote tumor immune evasion. Depletion of TAMs or modulation of their pro-tumoral functions are actively pursued, with the purpose of relieving this state of immune-suppression. We previously reported that trabectedin, a registered anti-tumor compound, selectively reduces monocytes and TAMs in treated tumors. However, its putative effects on the adaptive immunity are still unclear. In this study we investigated whether treatment of tumor-bearing mice with trabectedin modulates the presence and functional activity of T lymphocytes. In treated tumors there was a significant upregulation of T cell-associated genes, including CD3, CD8, Perforin, Granzyme B and IFN-responsive genes (MX1, CXCL10 and PD-1), indicating that T lymphocytes were activated after treatment. Notably, the mRNA levels of the Pdcd1 gene, coding for PD-1, were strongly increased. Using a fibrosarcoma model poorly responsive to PD-1-immunotherapy, treatment with trabectedin prior to anti-PD-1 resulted in improved anti-tumor efficacy. In conclusion, pre-treatment with Trabectedin enhances the therapeutic response to checkpoint inhibitor-based immunotherapy. These findings provide a good rational for the combination of trabectedin with immunotherapy regimens. This article is protected by copyright. All rights reserved.