Abstract 4444: Targeting eIF4F-mediated translation to reduce T cell exhaustion and enhance PD-1 blockade efficacy in melanoma

Abstract Background: The eukaryotic initiation factor 4F (eIF4F) complex is essential for the selective translational control of protein expression enabling cells to rapidly adapt to diverse stimuli. We previously identified an eIF4F/STAT1/PDL1 axis in melanoma cells. The effectiveness of cancer immunotherapy, particularly immune checkpoint inhibitors (ICIs) or tumor-infiltrating lymphocytes (TILs)-based adoptive therapy, is hindered by resistance mechanisms associated with the terminal exhaustion of T cells. Here, we investigate the role of eIF4F in the translational control of immune checkpoints (ICs) and associated transcription factors in both circulating T cells and TILs from melanoma patients, aiming to reveal potential connections between eIF4F-mediated translational regulation and T cell exhaustion. Methods: Polysome profiling was conducted on both circulating lymphocytes and TILs isolated from 10 melanoma specimens. We examined the expression of various activation/exhaustion markers by FACS, assessed T cell functions and determined cytokine secretion profiles. These experiments were performed with and without inhibition of the eIF4F-dependent translation using three different inhibitors of the eIF4A helicase (eIF4A-i: silvestrol, EFT226 and RBX0901). The effects of eIF4A-i combined with PD1 blockade were assessed in ex-vivo co-cultures, organotypic models and three syngeneic murine cancer models of melanoma and colon cancer. Results: Key negative immune checkpoints and transcription factors including TOX, NFAc2, CTLA-4, LAG3, and TIM3 are regulated by eIF4F in TILs and can be efficiently downregulated by eIF4A-i. Notably, the factors controlled by eIF4F in circulating CD8+ T cells differ from those in TILs emphasizing the importance of patients’ tumor-derived samples. TILs proliferation is increased by eIF4A-I in vitro. Co-culture experiments with TILs and syngeneic melanoma cells along with organotypic melanoma models, showed enhanced melanoma killing by TILs when anti-PD1 was combined with eIF4A-i. Additionally a synergistic effect of eIF4A and anti-PD1 was observed in the three immunocompetent murine models tested. Conclusion: Our findings unveil a previously unrecognized role of eIF4F in orchestrating the translational regulation of key proteins driving T cell exhaustion. This study is the first to demonstrate that targeting eIF4F with eIF4A inhibitors not only downregulates exhaustion markers but also synergistically enhances the efficacy of anti-PD-1 therapy across multiple models, including human TILs and murine cancer systems. This novel insight underscores the immense therapeutic potential of combining eIF4A inhibitors with ICIs to overcome resistance mechanisms and reinvigorate anti-tumor immunity. Citation Format: Samad Muhammadnejad, Monireh Kazemimanesh, Naima Benannoune, Sandrine Agoussi, Cecile Badoual, Louis Vaquier, Helene Lecourt, stéphan Vagner, caroline Robert. Targeting eIF4F-mediated translation to reduce T cell exhaustion and enhance PD-1 blockade efficacy in melanoma [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 4444.