Abstract B019: Inhibition of the CXCR1 and CXCR2 chemokine receptors synergizes with docetaxel to remodel the tumor-immune microenvironment and effectively control tumor growth

Abstract Overexpression of the chemokine receptors CXCR1, CXCR2, and their ligands CXCL1/2/3/5/6/7/8 in several tumor types has been shown to promote mechanisms of tumor progression while subsequently driving resistance to chemotherapy and immunotherapy. CXCR1/2 receptor-associated signaling pathways have been shown to drive therapeutic resistance through the promotion of tumor angiogenesis, induction of tumor cell plasticity leading to increased tumor cell migration, invasiveness, and resistance to cell death, and chemoattraction of polymorphonuclear (PMN)-MDSC to the tumor microenvironment. In this study, the chemokine receptors CXCR1 and CXCR2 were evaluated as potential novel targets for the treatment of HPV-negative and HPV-positive HNSCC and advanced prostate cancer, in combination with the chemotherapy docetaxel. Our analysis of HNSCC tissues via RNA in situ hybridization, RT-PCR, and Western blot analysis revealed that high levels of IL-8, CXCR1, and CXCR2 expression were present in HPV-negative compared to HPV-positive HNSCC tumors or cell lines. Treatment of HPV-negative HNSCC cell lines in vitro with a clinical stage CXCR1/2 small molecule inhibitor, SX-682, sensitized tumor cells to the cytotoxic activity of microtubule-targeting docetaxel but not the alkylating agent cisplatin. Furthermore, treatment of multiple HNSCC xenograft models in vivo with the combination of CXCR1/2 inhibition plus docetaxel led to strong anti-tumor control resulting in tumor cures. This phenomenon was associated with an increase of microRNA-200c and a decrease of tubulin beta-3, a protein involved in resistance to microtubule-targeting chemotherapies. Additionally, in vivo treatment of both the MOC1 and MOC2 murine syngeneic models of HNSCC with CXCR1/2 inhibition plus docetaxel led to potent anti-tumor efficacy. Analysis of the TME via flow cytometry and bulk RNA sequencing revealed a simultaneous decrease in suppressive CXCR2+ PMN-MDSC and an increase in cytotoxic CD8+ T cells in tumors treated with the combination therapy compared to the controls and each of the monotherapies. In an effort to highlight the efficacy of this combination therapy across a variety of tumor types which express high levels of IL-8 ligands, we have also observed potent anti-tumor control of the combination therapy using CXCR1/2 inhibition plus docetaxel in multiple xenograft and allograft models of prostate cancer in mice.This study reports the mechanistic findings through which the combination of CXCR1/2 inhibition and docetaxel exhibits synergy, and has provided rationale for the use of this novel combination approach to treat advanced HNSCC and prostate cancer patients. Future studies will be conducted to evaluate the addition of other immunotherapy agents to the combination of CXCR1/2 inhibition and docetaxel. Citation Format: Lucas A. Horn, Hanne Lind, Kristen Fousek, Haiyan Qin, Nika Rajabian, Shantel Angstadt, Nicole Hsiao-Sanchez, Miriam M. Medina-Enriquez, Marcus D. Kelly, Dean Y. Maeda, John A. Zebala, Claudia Palena. Inhibition of the CXCR1 and CXCR2 chemokine receptors synergizes with docetaxel to remodel the tumor-immune microenvironment and effectively control tumor growth abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B019.