Abstract 6037: Circulating CD8 T-cell responses to neoantigens predict responsiveness to PD-(L)1 axis blockade in non-small cell lung cancer

Abstract Tumor-specific T cells play a central role in tumor control, yet the attainment of their full tumor rejection potential is hindered by regulatory mechanisms, including expression of inhibitory immune checkpoints. Although immunotherapy by immune checkpoint blockade (ICB) has transformed cancer care, only a proportion of patients experience clinical benefit. Ancillary studies to clinical trials evaluating ICB have revealed an association between high tumor mutational burden (TMB) and treatment efficacy, suggesting that unleashing T cells targeting neoepitopes encoded by somatic mutations could underlie ICB-mediated tumor control or regression. Nevertheless, TMB or tumor neoantigenic burden (TNB) are not consistently related to clinical response, potentially because most studies have addressed the influence of TMB and TNB by in silico prediction without systematic analysis of actual neoantigen-specific T cells. We hypothesized that the presence of actual neoantigen-specific T-cell responses would predict response to ICB, rather than the mere presence of a high TMB or TNB. Using whole exome and transcriptome sequencing in a cohort of 29 non-small cell lung cancer patients receiving anti-PD-1/PD-L1, we assessed expressed non-synonymous exonic mutations in each patient's tumor and predicted the encoded neoepitopes restricted by each patient's HLA-I and -II alleles. In our cohort, HLA-I TNB was better correlated to clinical response and progression free survival (PFS) than TMB and HLA-II TNB. We developed a workflow allowing for the assessment of circulating CD8 T-cell responses to more than 400 prioritized neoepitopes, and to 50 long peptides harboring each several predicted CD4 neoepitopes containing the same mutated amino acid. We showed, in 28 patients from whom PBMCs were available, that circulating CD8 T-cell responses to predicted neoantigens were of higher magnitude and breadth in clinical responder compared to non-responder patients. The presence of a CD8 T-cell response to neoantigens was associated with better PFS. No correlation was observed between expressed TMB or TNB (HLA-I or -II) and the magnitude of CD8 or CD4 T-cell responses. Longitudinal ex vivo enumeration of neoantigen-specific CD8 T-cells using HLA/peptide tetramers showed that they had a memory phenotype and that they experienced significant proliferation under therapy. Our results ascertain the contribution of neoantigen-specific CD8 T-cells in therapeutic tumor rejection. They also provide an opportunity, through the analysis of tumor molecular signatures, to unveil the mechanisms supporting or restraining the priming of spontaneous T-cell responses targetable by ICB. This research was a collaborative effort by sites within the imCORE network, made possible through support from F.Hoffmann-La Roche. Citation Format: Célia Ramade, Noémie Thébault, Clara-Maria Scarlata, Françoise Lauzéral-Vizcaino, Caroline Fournier, Victor Sarradin, Anna Salvioni, Marie Michelas, Daniel Oreper, Suchit Jhunjhunwala, William Thrift, Adric Quade Broadwell, Nicolas Lounsbury, Kai Liu, Meng Xiao He, Martine Darwish, Catherine Ross, Hang Xu, Milena Hornburg, Amy Heidersbach, Fanny Bouquet, Catia Fonseca, Laetitia Tudeau, Nicolas Congy-Jolivet, Carlos Gomez-Roca, Thomas Filleron, Lélia Delamarre, Julien Mazières, Jean-Pierre Delord, Maha Ayyoub. Circulating CD8 T-cell responses to neoantigens predict responsiveness to PD-(L)1 axis blockade in non-small cell lung cancer [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 6037.