Abstract 3963: Indoleamine 2,3-dioxygenase 1 (IDO1) regulates immune evasion in lymphoma

Abstract Recently, anti-programmed death (anti-PD) therapy has been at the forefront of cancer therapy. However, the clinical efficacy of anti-PD therapy in DLBCL remains obscure. The marginal response to anti-PD therapy in DLBCL indicates that different mechanisms of immune evasion other than the PD-1/PD-L1 pathway may be present. To investigate the mechanisms of resistance to anti-PD therapy in DLBCL, we assessed gene expression in patients with DLBCL in public database. Accordingly, we found indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme responsible for tryptophan catabolism, is highly expressed in DLBCL. IDO1 expression is upregulated by IFN-gamma produced by T cells in tumor microenvironments (TMEs) of various cancer types. Upregulated IDO1 leads to the production of kynurenine, which creates an immunosuppressive TMEs. However, it remains unknown whether IDO1 induces immune evasion in DLBCL and if so, which subsets of IDO1 expressing cells are responsible for immune evasion in DLBCL. To address these questions, we first determined the intrinsic role of IDO1 in lymphoma cells. We knocked down IDO1 expression (IDO1 KD) in a human DLBCL RC-K8 cell line using short hairpin RNA. We observed decreased cell proliferation in IDO KD lymphoma cells compared with control cells. We also found increased susceptibility to apoptosis in IDO1 KD RC-K8 cells compared with IDO1 WT control, when these were co-cultured with THP-1-derived macrophages or activated Jurkat T lymphocytes. These data suggest that lymphoma IDO1 has an intrinsic role of lymphoma progression and makes lymphoma sensitive to cytotoxic immune cells. To validate the anti-tumor effect of IDO1 deficiency in immune cells, we assessed EL4 lymphoma growth and immune TME of lymphoma in syngeneic wild type (WT) and Ido1 knock-out (KO) mice. The growth of EL4 lymphoma tumor was significantly suppressed in Ido1 KO mice compared to WT mice (Ido1 KO: 621.9mm3 vs WT: 1228mm3, N=22, P<0.001). Immune TME assessment revealed a decreased frequency of regulatory T cells, yet, the increased proportions of B cells, MHC II+ antigen-presenting cells, monocytes, and NK cells in Ido1 KO tumors compared with WT control. In summary, IDO1 is highly expressed in DLBCL. IDO1 up-regulation may drive lymphoma progression both intrinsically and extrinsically (immune evasion). This data suggests that IDO1 overexpression may be one of the mechanisms of resistance to anti-PD therapy. We will extend our studies to determine a combination effect of IDO1 inhibitors with immune checkpoint inhibitors including anti-PD therapy in DLBCL. Citation Format: Jihyun Park, Seung-Joo Yoo, Qianni Hu, Carly M. Fielder, Hyundong Yoon, Junshik Hong, Byung-Su Kim, Youngil Koh, Tae Kon Kim, Sung-Soo Yoon, Chi Yan. Indoleamine 2,3-dioxygenase 1 (IDO1) regulates immune evasion in lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3963.