Elderly lung cancer patients show tumor-infiltrating CD8+ T Cell responses enriched with PDCD1 and CXCL13 after neoadjuvant therapy with Anti-PD-1

Aims: Aged individuals are significantly underrepresented in immunotherapy clinical trials for cancer. Little is known regarding the immunological and molecular dynamics that might regulate their responsiveness to immune checkpoint inhibitors (ICIs). This study aims to investigate the mechanisms affecting the response of elderly non-small cell lung cancer (NSCLC) patients to anti-PD-1 therapy. Methods: We performed a single-cell analysis on public data from 419,107 tumor-infiltrating lymphocytes (TILs) across 11 elderly (≥ 65 years) and 5 non-elderly NSCLC patients treated with neoadjuvant anti-PD-1 therapy. The dataset, originally focused on mutation-associated neoantigen-specific T cells, was reprocessed to compare gene expression and molecular patterns associated with positive outcomes and tumor clearance between age groups. Results: The analysis revealed that ICI responsiveness was not impaired by age, and T cell immunosenescence was observed in aged (≥ 65 years) and younger NSCLC individuals. Both elderly and young individuals produced responses with a heterogeneous molecular program associated with tumor-reactive CD8+ TILs. Specifically, T cells from elderly patients showed an enhanced expression of PDCD1 and CXCL13 (P < 0.001) in comparison to younger subjects. Conclusion: Altogether, our findings demonstrate favorable molecular signatures in aged NSCLC individuals following anti-PD-1 treatment and suggest that the recruitment of older adults in immunotherapy clinical trials should not be dismissed solely on the grounds of age.