Abstract 7456: Overcoming ICI resistance with CXCR1/2 antagonism in advanced HCC
Authors: Jeric Hernandez, Kabeer Munjal, Emma Kartalia, Madelena Brancati, Howard L. Li, James Leatherman, Ervin Griffin, Christopher J. Thoburn, Won Jin Ho, Marina Baretti, Daniel J. Zabransky, Elizabeth M. Jaffee, Mark Yarchoan, Mari Nakazawa
Journal: Cancer Research (2025)

Abstract Background: Despite the recent success of immune checkpoint inhibitor (ICI) based regimens in advanced stage HCC, clinical outcomes remain poor with a median overall survival (OS) of under two years. There is an unmet need to improve responses to, and durability of, ICI based therapy in HCC. IL-8 is a chemokine promoting the attraction of myeloid cells via receptor CXCR1/2 and has been shown to have numerous pro-tumorigenic roles in the tumor immune microenviroment (TiME). Recent work by others has shown that high plasma IL-8 concentration is associated with inferior outcomes for patients receiving ICI therapy across multiple solid tumors, but its relevance to outcomes in patients with HCC is not well characterized. Methods: We prospectively collected whole blood from patients with HCC prior to initiation of standard of care immunotherapy-based regimens at Johns Hopkins (IRB #00267960). Plasma cytokines were profiled via Luminex bead-based immunoassay. To profile the local effects of IL-8 on the TiME, we performed IHC (anti-IL8, anti-CD3, anti-CD8, and anti-CD206) on resected HCC tumor tissue from systemic treatment naive patients (n=13). Finally, to understand the consequences of IL-8 inhibition via CXCR1/2 antagonism, we utilized a syngeneic murine HCC model (RIL-175 in female C57BL/6) treated with medicated SX-682 (anti-CXCR1/2) alone and in combination with intraperitoneal injections of anti-PD1+anti-VEGF. Results: The final clinical cohort included 41 patients with advanced HCC. Patients were predominantly male (82.9%) with Barcelona Clinic Liver Cancer (BCLC) stage C disease (75.6%) who received treatment with atezolizumab + bevacizumab (51.2%). In a multivariable Cox model, baseline plasma IL-8 above or equal to median was associated with inferior progression free survival (PFS; hazard ratio [HR] 3.78, p=0.01) and OS (HR 2.32, p=0.07) after controlling for BCLC stage, albumin-bilirubin (ALBI) index, baseline alpha fetoprotein (AFP), regimen type, and baseline concentration of other cytokines with relevance in HCC (IL-6, IL-10, and VEGF-A). IHC on resected tumor specimens revealed negative correlation between IL-8 staining and CD8 cell density (R=-0.2, p=0.041) and positive correlation with CD206 staining (R=0.24, p=0.05). In our murine model, combination treatment with anti-CXCR1/2, anti-PD1, and anti-VEGF was associated with reduction of tumor volume at day 36 compared to control (p&amp;lt;0.001), anti-CXCR1/2 (p=0.006) and anti-PD1+anti-VEGF (p=0.06). Conclusions: Consistent with prior reports in other solid tumors, high plasma IL-8 concentration was associated with inferior survival on ICI based regimens in HCC. We hypothesize that IL-8 signaling promotes M2 macrophage polarization and in turn results in reduced effector T cell infiltration in the TiME. These results provide rationale for targeting the CXCR1/2 signaling axis in advanced HCC. Citation Format: Jeric Hernandez, Kabeer Munjal, Emma Kartalia, Madelena Brancati, Howard L. Li, James Leatherman, Ervin Griffin, Christopher J. Thoburn, Won Jin Ho, Marina Baretti, Daniel J. Zabransky, Elizabeth M. Jaffee, Mark Yarchoan, Mari Nakazawa. Overcoming ICI resistance with CXCR1/2 antagonism in advanced HCC [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 7456.