Abstract
The impact of non-small cell lung cancer (NSCLC) tumor metabolism on the immune microenvironment is not well understood in the context of platinum resistance. We have identified and characterized crucial metabolic differences between cisplatin-resistant (CR) and cisplatin-sensitive (CS) NSCLC cells in which CR cells possessed higher indoleamine 2,3-dioxygenase-1 (IDO1) activity as determined by an increase in extracellular kynurenine concentration in vitro and in vivo. Utilizing in vitro co-culture models (n=6), we showed that IDO-mediated kynurenine production from CR cells suppressed natural killer group 2 member D (NKG2D) on natural killer (NK) and CD8+ T cells, but enhanced immunosuppressive regulatory T cell (Treg) and myeloid-derived suppressor cells (MDSC) populations. Utilizing syngeneic (n=7) and humanized (n=5) mouse models, mice with CR tumors exhibited a more highly immunosuppressive environment that blocked the antitumor immune response. Inhibition of IDO1 by the selective IDO1 inhibitor epacadostat (200 mg/kg P.O. once a day for 15 days) attenuated tumor growth in these CR tumor-bearing mice. Interestingly, we found an induction of tryptophan 2,3-dioxygenase-2 (TDO2) enzyme in epacadostat-treated mice. To overcome this compensatory effect induced by IDO1 inhibition, mice were treated with a novel IDO1/TDO2 dual inhibitor (AT-0174; Antido Therapeutics Pty Ltd, Melbourne, Australia) at 170 mg/kg P.O. once a day for 15 days. Dual inhibitors suppressed tumor growth to a greater degree than IDO1 inhibitors in CR conditions, and significantly enhanced immune effector populations as well as suppressed immunosuppressive Tregs and MDSC population in CR tumors. In addition, increased expression of programmed death-ligand 1 (PD-L1) was observed in CR cells, we assessed the effects of combination treatment of AT-0174 + anti-PD1 antibody. This combined therapy produced a profound anti-tumor effect in CR tumors and extended survival in mice. Our data support an increase in the therapeutic efficacy of blocking both IDO1/TDO2 in treating CR lung cancer by enhancing tumor immune surveillance. Thus, inhibiting the kynurenine pathway may be a more suitable therapeutic approach in a subgroup of lung cancer patients who failed platinum therapy and lead to improved outcomes in the treatment and management of NSCLC. Support by Dept. of Veterans.
Citation Format: Sydney Spector, Chunjing Wu, George Theodore, Jonathan Dan Nguyen, Emily Kim, Ashley Garcia, Niramol Savaraj, Diane Lim, Lynn Feun, Medhi Wangpaichitr. Targeting IDO1 and TDO2 is crucial for the modulation of immune effector in platinum resistant non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5886.