Abstract 2821: TRIB2 regulates immune evasion in antiandrogen-resistant and neuroendocrine prostate cancer

Abstract Background: Enzalutamide resistance remains a major clinical challenge in advanced prostate cancer. We previously identified Tribbles homolog 2 (TRIB2) as highly upregulated in enzalutamide-resistant prostate cancer (ERPC), including neuroendocrine (NE)-type resistant tumors, where it drives tumor cell survival, lineage plasticity, and therapeutic resistance. Targeting TRIB2 suppresses the growth of resistant cells, highlighting its critical role in disease progression. Immune checkpoint molecules, including B7-H3 (CD276) and PD-L1 (CD274), are also elevated in ERPC and NE prostate tumors and contribute to impaired T cell-mediated anti-tumor immunity. These convergent findings led us to hypothesize that TRIB2 promotes immune evasion in treatment-resistant prostate cancer and that its inhibition may enhance T-cell-mediated anti-tumor immunity. Methods: Enzalutamide-resistant (C4-2BENZR and LNCaPENZR) and NE (NCI-H660) prostate cancer cell lines were used to investigate TRIB2-dependent immune regulation. TRIB2 expression was modulated using lentiviral shRNA knockdown, plasmid-mediated overexpression, or pharmacological inhibition using the selective TRIB2 inhibitor TBI-001. B7-H3 and PD-L1 expression was measured using western blot and flow cytometry. Modified cancer cells were co-cultured with activated human CD8+ T-cells, and T-cell activation, cytokine production, and cytotoxicity were evaluated using standard immunological assays. Results: Both TRIB2 knockdown and TBI-001 treatment markedly reduced B7-H3 and PD-L1 expression in ERPC and NE prostate cancer cells, whereas TRIB2 overexpression increased immune checkpoint levels. TRIB2 inhibition enhanced CD8+ T-cell activation and cytokine secretion (IFN-γ and TNF-α), and improved T cell-mediated cytotoxicity against resistant cancer cells. Conversely, cells with elevated TRIB2 levels strongly suppressed T-cell activation and cytotoxicity. Immune checkpoint blockade partially restored T-cell function against TRIB2-high cells, with combined blockade showing enhanced effects in restoring anti-tumor immunity. Conclusion: These findings demonstrate that TRIB2 facilitates immune evasion in enzalutamide-resistant and neuroendocrine prostate cancer by upregulating immune checkpoint proteins and suppressing anti-tumor T-cell activity. This represents a dual mechanism by which TRIB2 drives treatment-resistant prostate cancer progression through both tumor-intrinsic effects and modulation of the tumor microenvironment. Therapeutic targeting of the TRIB2-immune checkpoint axis represents a rational strategy to overcome enzalutamide resistance, offering the combined benefit of inhibiting tumor growth while restoring effective anti-tumor immunity. Citation Format: Sharad K. Suthar, Azizur Rahman, Sang-Yoon Lee, Jitender Monga. TRIB2 regulates immune evasion in antiandrogen-resistant and neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2821.