Pre-immunotherapy alters stereotactic ablative radiotherapy-induced systemic T cell responses in early-stage NSCLC.

Background: Stereotactic ablative radiotherapy (SABR) is thought to activate T cell responses in patients with cancer, leading to its combination with immunotherapy and chemotherapy for treatment of non-small-cell lung cancer (NSCLC). Here, we aimed to provide a high-resolution transcriptomic profiling of the systemic T cell response following SABR, with or without preceding immunotherapy/chemotherapy.

Methods: We conducted single-cell RNA and T cell receptor (TCR) sequencing of T cells from peripheral blood of seven patients with early-stage NSCLC taken pre- and post-SABR without or with prior immunotherapy and chemotherapy (icSABR). Other flow cytometry, single-cell RNA-seq data and bulk RNA-seq data were used to validate the results.

Results: We uncovered distinct T cell response patterns induced by these treatments: while terminal effector CD8⁺ T cells showed increased cytotoxic and inhibitory scores, and upregulated immune-activated pathways post-SABR, the reverse responses occurred post-icSABR. Furthermore, the proportion of large T cell clones increased and single clone decreased post-SABR, while the opposite was seen post-icSABR. Of note, both SABR and icSABR largely changed TCR clonotypes, which were mainly large clones post-SABR but single clone post-icSABR, and predominantly from terminal effector CD8⁺ T cells and T helper cells, respectively.

Conclusions: These findings reveal a complex interplay between SABR and immunotherapy, with potentially valuable implications for treatment strategies involving SABR and immunotherapy to induce systemic T cell responses for tumor eradication in patients with NSCLC.