Abstract 2190: Genomic scarring score is associated with T cell exhaustion in early stage non small cell lung cancer

Abstract Introduction: We have recently reported that almost a third of the patients in an early stage NSCLC cohort harbor a high genomic scarring score (GSS) indicating HRD. Immunotherapy is an attractive partner of PARP inhibitors (PARPi), especially in case of PARPi resistance. Immunotherapy-based regimens are shown to be highly efficient and provide significant clinical benefit in the pre- and peri-operative setting in early-stage NSCLC suggesting that the TME is permissive for the immunotherapy effect in this tumor type. Purpose: We wished to characterize the different subpopulations of tumor infiltrating lymphocytes (TILs) in early-stage NSCLC and correlate them with the clinical outcome. Methods: Next generation sequencing was used to evaluate the GSS of primary tumors from 136 early-stage NSCLC based on a commercially available sequencing kit which also provides information on the genetic status of relevant HRR and other genes (Amoy Dx) and patients were stratified as low (<50, l-GSS) or high (>50, h-GSS) GSS. Analysis of the tumor microenvironment (TME) immune infiltrate was performed by single and double staining ICH using monoclonal antibodies against T cells and B cells as well as PD1 and TCF1. Results: 39 (28.7%) and 97 (71.3%) tumors were h-GSS and l-GSS respectively. There was a marginal enrichment of somatic HRR gene mutations in the h-GSS compared to the l-GSS group but this was not statistically significant. There were no significant differences regarding the occurrence of co-mutations in the two groups except for TP53 which was significantly higher in h-GSS (94.4%) compared to l-GSS samples (51.5%; p<0.001). TIL immunophenotyping did not show significant differences regarding the CD8+, CD4+ and FOXP3+ T cells and CD79+ B cells. Expression of PD1+TCF1+ and PD1+TCF1-, namely progenitor and terminally exhausted T cells respectively, was significantly higher in the h-GSS (5.1 ± 5.1; 15.0 ± 12.3) compared to l-GSS (2.5 ± 2.2; 8.8 ± 7.2; p=0.037 and p=0.040) group. In the subgroup of patients who received adjuvant platinum-based chemotherapy the increased infiltration of tumor center with both PD1+TCF1- and PD1-TCF1+ cells was independently associated with DFS [HR=3.1 (p=0.040) and in these patients both DFS and OS was significantly improved in patients co-harboring a h-GSS with pathogenic/likely pathogenic TP53 mutations compared to patients with l-GSS/TP53wt (p=0.012 and p=0.032, respectively). Conclusions: Our data demonstrate for the first time that a significant percentage of early-stage NSCLC patients exhibit genomic instability (h-GSS) which is associated with a unique TP53 status and the immune profile of the exhaustion state. The latter highlights the heterogeneity of the different subpopulations of exhausted TILs in the TME of NSCLC, which seems to have substantial prognostic and predictive clinical relevance especially in patients with h-GSS. Citation Format: Ioannis Pateras, Konstantinos Ntostoglou, Georgios Christodoulopoulos, Katerina Tsilingiri, Anna Chalari, Giannis Vatsellas, Georgia Christopoulou, Pantelis Constantoulakis, Eleni Patsea, Konstantinos Potaris, Ioannis Vamvakaris, Dora Chatzidaki, Georgina Zachou, Athanasios Kotsakis, Apostolos Klinakis, Vassilis Georgoulias. Genomic scarring score is associated with T cell exhaustion in early stage 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 2190.