Abstract 4094: Immune modulatory cancer vaccines against IDO1 and PD-L1 trigger distinct pathways and cooperatively reduce tumor growth in preclinical models

Abstract

Abstract While immune checkpoint inhibitors have shown clinical efficacy in many cancers, drug and immune resistance remain challenging. Indoleamine 2,3-dehydrogenase (IDO1) and Programmed Death Ligand 1 (PD-L1) both contribute to immunosuppression, leading to immune escape and cancer progression. In this context, vaccination to promote T-cell immunity against IDO1+ and PD-L1+ cells is an attractive strategy that demonstrated encouraging clinical results in melanoma (Kjeldsen et al. Nat Med 2021). Our study aims to further evaluate the efficacy and mode of action of combined IDO1 and PD-L1 peptide vaccines. Mice injected with tumor cells and treated with IDO1 or PD-L1 peptides were monitored for tumor growth. Vaccine activity was determined by IFNγ Elispot assay. Gene expression analysis was performed on tumors using Nanostring nCounter PanCancer IO360 Panel. IDO1 and PD-L1 expression were also examined via multiplex immunofluorescence in a human tumor tissue microarray (TMA) panel. Human IDO1 and PD-L1 specific CD4+ T cell clones were isolated and expanded from melanoma patients treated with IDO1/IO102 or PD-L1/IO103 peptide vaccines in combination with aPD1 therapy. Immunofluorescence analysis of murine tumor sections showed expression of IDO1 and PD-L1 by different cell populations. Vaccination against each target led to expansion of specific T cells in splenocytes and reduced tumor growth in MC38 and CT26 models. Combining IDO1 and PD-L1 treatments further enhanced the anti-tumor response. Gene expression analysis of tumors revealed distinct signatures following monotherapy and combination treatments. While PD-L1 vaccination predominantly enhanced the cytotoxic effector T cell function in the tumor microenvironment (TME) and concomitantly increased gene signatures associated with enhanced activation of T effector cells, IDO1 vaccine primarily exerted its effect via reduction in the immune suppression loop. TMA analysis of IDO1+ and PD-L1+ cells in human tumors also revealed that they represent largely distinct cell populations. Lastly, IDO1 and PDL1-specific CD4+ T cell clones from melanoma patients treated with IO102-IO103 vaccine could selectively target cells differentially expressing IDO1 or PDL1. Our data collectively show that cells expressing IDO1 and PD-L1 represent distinct populations in the TME thus targetable by the IDO1-PD-L1 vaccination approach. The vaccines targeting IDO1 and PD-L1 cooperatively reduce tumor outgrowth, and each contributes to the anti-tumor effect through distinct molecular programs regulating immunosuppression in the TME and T cell activation respectively. These data are supported by ex vivo functional assays using target specific T cells from vaccinated patients. Altogether, our data support the use of a dual antigen approach to reduce the immunosuppression and enhance anti-tumor effect. Citation Format: Marion Chapellier, Evelina Martinenaite, Preeyam Patel, Lea Svendsen, Shamaila Munir Ahmad, Hannah Jorinde Glöckner, Marco Carretta, Erika Sutanto-Ward, James DuHadaway, Souvik Dey, Shih-Chun Shen, Dema Ghaban, Marcos Iglesias, Megan Biller, Inés Lecoq, Alexander J. Muller, Mads Hald Andersen, Ayako Wakatsuki Pedersen. Immune modulatory cancer vaccines against IDO1 and PD-L1 trigger distinct pathways and cooperatively reduce tumor growth in preclinical models [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 4094.