Camptothesome Potentiates PD-L1 Immune Checkpoint Blockade for Improved Metastatic Triple-Negative Breast Cancer Immunochemotherapy.

Abstract

In this study, we focus on investigating the therapeutic effects of camptothesome on treating metastatic triple-negative breast cancer (TNBC). We elucidate that camptothesome elicited stronger immunogenic cell death (ICD) compared to free camptothecin (CPT) and Onivyde in 4T1 TNBC cells. In addition, camptothesome is mainly internalized by the 4T1 and MDA-MB-231 cells through clathrin-mediated endocytosis based on the results of flow cytometry. Through real-time Lago optical imaging, camptothesome shows excellent tumor-targeting efficiency in orthotopic TNBC tumors. We demonstrate that camptothesome can upregulate programmed death-ligand 1 (PD-L1) in 4T1 tumors in an interferon gamma (IFN-γ)-dependent manner. Furthermore, the anti-TNBC efficacy studies reveal that camptothesome is superior to Onivyde and markedly potentiates PD-L1 immune checkpoint blockade therapy with complete lung metastasis remission in an orthotopic 4T1-Luc2 tumor model. This combination therapy eliciting robust cytotoxic T lymphocytes (CTL) response via boosting tumor-infiltrating cluster of differentiation 8 (CD8), calreticulin (CRT), high mobility group box 1 protein (HMGB-1), low-density lipoprotein receptor-related protein 1 (LRP1), IFN-γ, and granzyme B. Our work corroborates the promise of camptothesome in favorably modulating tumor immune microenvironment via inducing ICD to fortify the PD-L1 checkpoint blockade therapy for improved treatment of intractable TNBC.