Abstract 4879: Unveiling a key obstacle to effective antitumor immunity in T-cell-restricted tumors

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Abstract Endogenous antitumor immune responses in cancer patients can lead to the formation of "inflamed" tumors, characterized by a significant infiltration of tumor-reactive T cells. However, the majority of patients fail to mount such robust immune responses, resulting in immune-evasive tumors. To explore the mechanisms underlying this failure, we established and compared spontaneous mouse models of hepatocellular carcinoma (HCC) with either an inflamed, T-cell-rich or non-inflamed, T-cell-deprived tumor microenvironment (TME). Intriguingly, non-inflamed tumor models exhibited splenomegaly and elevated plasma erythropoietin (EPO) levels despite the absence of anemia, and these effects were independent of tumor size. This finding raised the possibility that tumor-derived EPO might dictate tumor immunotype. Our investigations revealed that EPO ablation in non-inflamed HCC models led to a substantial increase in effector memory CD8 T-cell infiltration, reduced tumor burden, and even induced tumor regression. Conversely, enforced EPO expression in inflamed HCC models suppressed T-cell infiltration and promoted tumor progression. Further analysis of both human and mouse HCC tissues demonstrated that the erythropoietin receptor (EPOR) is predominantly expressed on tumor-associated macrophages (TAMs). Tumor-derived EPO interacts with EPOR on TAMs to autonomously establish a non-inflamed, immunosuppressive TME, effectively evading T-cell surveillance. Mechanistically, EPO-EPOR signaling reprograms TAMs toward an immunoregulatory phenotype via NRF2-mediated heme depletion. Disruption of this axis—through either tumor-derived EPO ablation or EPOR deletion on TAMs—transformed the TME into an inflamed, T-cell-rich TME, driving tumor regression regardless of tumor genotype. Notably, this immune reactivation synergized with immune checkpoint blockade therapy. In summary, the EPO/EPOR axis functions as a critical immunosuppressive switch, enabling tumors to escape immune surveillance. Its inactivation reprograms macrophages to foster antitumor immunity, offering a promising strategy to enhance the efficacy of immunotherapy in HCC and potentially other cancers. Citation Format: David Kung-Chun Chiu, Xiangyue Zhang, Bowie Yik-Ling Cheng, Kazukuni Hayashi, Qiang Liu, Bo Yu, Ryan Lee, Catherine Zhang, Jayakumar Rajadas, Nathan E Reticker-Flynn, Erinn B Rankin, Edgar G Engleman. Unveiling a key obstacle to effective antitumor immunity in T-cell-restricted tumors [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 4879.

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