Abstract A19: Metronomic chemotherapy enhances immunotherapy by preventing stroma-induced immunosuppression

Abstract

Abstract Chemotherapy (C/T) drugs are usually administered to cancer patients every few weeks at a high, “maximum tolerated” dose (MTD). Though this approach kills the majority of tumor cells, it often spares a small number of stem-like cancer cells (CSCs) that subsequently give rise to new tumors. Moreover, these recurring tumors are often more aggressive and able to metastasize to other tissues, in part because high doses of C/T drugs also affect cells in the stromal tissue that surrounds tumors, including carcinoma-associated fibroblasts (CAFs) and immune cells. Many human solid tumors are characterized by a pronounced stromal reaction characterized by a desmoplastic response produced by CAFs as well as an extensive infiltration by immunosuppressive cell populations such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Importantly, both the tumor epithelium and adjacent stroma respond to systemic C/T and a therapy-modified stroma can deleteriously influence treatment efficacy. Recently, we have demonstrated in assorted mouse tumor models that traditional C/T using the MTD regimens of C/T agents such as cyclophosphamide, doxorubicin, gemcitabine, and paclitaxel could paradoxically render CAFs oncogenic through the stromal-epithelial ELR+-chemokine/CXCR-2 signaling axis, which expands CSCs, enhances tumor neovascularization, and induces immunosuppressive M2 subtype TAM infiltration, together leading to tumor recurrence and treatment refractoriness (Chan et al., J. Exp. Med 2016). By contrast, the same total accumulated dose of the C/T agents administered as a low-dose metronomic (LDM) regimen could largely prevent the therapy-induced stromal alterations and CSC expansion and thereby substantially enhance the treatment response. We subsequently showed that LDM C/T not only obviated the MTD-C/T-elicited CSC expansion but also attenuated the influx of the highly immunosuppressive granulocytic MDSCs, thereby potentiating immunotherapy such as anti-PD-1. We thus anticipate that, while pharmacologic inhibition of CXCR-2 has enhanced the antitumor efficacy of immune checkpoint blockade, LDM C/T may provide a clinically applicable alternative of enhancing immune surveillance in stroma-rich and T-cell inflamed tumors. Collectively, our studies provide compelling evidence and novel mechanistic insights into the unique benefit of LDM C/T on the tumor stroma. Given that MTD C/T exerts favorable influences on tumor stemness and immunity, it may better synergize with emerging CSC-targeted or immunotherapeutics than traditional MTD C/T to further enhance the therapeutic outcome of human solid tumors. Citation Format: Kelvin K. Tsai, Tze-sian Chan. Metronomic chemotherapy enhances immunotherapy by preventing stroma-induced immunosuppression [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A19.