Abstract 6133: Investigating the role of CXCR2 in NK cells in head and neck cancer
Authors: Lindsey M. Bachmann, Donatien Kamdem Toukam, Maria Lehn, Sam Nusbaum, Katelyn Jansen, Vinita Takiar, Dalia El-Gamal, Trisha Wise-Draper
Journal: Cancer Research (2025)

Abstract Head and neck cancer (HNC) is the sixth most common cancer globally, with 90% of HNC comprised of head and neck squamous cell carcinoma (HNSCC). Despite improvements in anticancer therapies, long-term survival rates for patients with advanced-stage HNSCC have remained stagnant for 30 years. Although the field of immunotherapy has primarily focused on the adaptive immune response, accumulating evidence suggests that natural killer (NK) cells are also important. Activation of the C-X-C chemokine receptor 2 (CXCR2) signaling axis has been implicated as a negative prognostic factor in many cancers, including HNSCC. Inhibition of CXCR2 results in reduction of tumor growth and increased infiltration of NK and T cells at least partially through suppressing myeloid derived suppressor cell (MDSC) recruitment. Our laboratory has recently demonstrated that the CXCL1/CXCR2 axis inhibits antitumor functions, including a direct attenuation of NK cellular cytotoxicity ex vivo, thereby promoting immune resistance and tumor growth. Here we investigate the effects of pharmacologic or genetic inhibition of CXCR2 in vivo using established murine oral cavity tumor models. Wild type C57BL/6 mice were injected into the buccal region with 1.5 x 106 mouse oral cavity (MOC-1) cells. Once tumors reached 50-150mm3, mice were treated by IP injection 3 times per week for 3 weeks with either vehicle, 10mg/kg of CXCR2 inhibitor (SB225002), 1µg/kg of CXCL1, or the combination. Mice that were treated with the CXCR2 inhibitor (CXCR2i) had decreased tumor growth, increased immune cell infiltration (NK and T cells), and increased anti-tumor cytokines such as IFN-γ and IL-1β in the serum. Interestingly, the antitumor effects of the CXCR2i were abrogated by the addition of CXCL1. Furthermore, to determine if NK and/or T cells contributed to CXCR2i-mediated tumor control, C57BL/6 mice were injected into the flanks with MOC-1 tumors as detailed above and treated with either vehicle or CXCR2i in the presence or absence of antibodies to deplete NK and/or CD8+ T cells. Again, the observed decrease in tumor growth was abrogated in mice depleted of NK cells, CD8+ T cells, or both NK and CD8+ T cells suggesting that both cytotoxic cell types are important for inhibiting tumor growth upon CXCR2 blockade. Visualization of immune cell infiltration within tumor sites via multiplex immunofluorescence staining is ongoing. Next, we explored genetic inhibition of CXCR2 in vivo. Interestingly, MOC-1 cells injected into the flanks of C57BL/6 mice in which Cxcr2 was globally knocked out had a paradoxical effect of enhanced tumor growth, suggesting that CXCR2 may be important during development for immune cell function. Studies are ongoing to examine how NK cell-specific CXCR2 knockout influences HNSCC tumor progression using an NK cell conditional Cxcr2 knockout murine model. These preliminary results suggest that the CXCL1/CXCR2 axis is in fact important for HNSCC tumor control. Citation Format: Lindsey M. Bachmann, Donatien Kamdem Toukam, Maria Lehn, Sam Nusbaum, Katelyn Jansen, Vinita Takiar, Dalia El-Gamal, Trisha Wise-Draper. Investigating the role of CXCR2 in NK cells in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6133.