Patterns of Immunity Changes Predict Response to SABR in Early Non-Small Cell Lung Cancer

SABR for early-stage non-small cell lung cancer (NSCLC) can stimulate an immune response against cancer. We evaluated changes in peripheral lymphocyte subpopulations and cytokine levels after SABR in patients with early-stage NSCLC. We examined how these changes relate to overall survival (OS) and disease-free survival (DFS).

Ninety-four patients with treatment-naïve NSCLC at stage T1/2aN0M0 were prospectively analyzed. Circulating lymphocytes were collected before treatment (TP1), at 2 weeks (TP2), and 12 weeks (TP3) after SABR. Using flow cytometry, we assessed the T-lymphocyte subpopulations expressing CD4, CD8, CD25, CD28, PD-1, CTLA-4 markers, ROR-γt, FoxP3, GATA3, T-bet transcription factors and, for a subgroup of 59 patients, serum Th1, Th2, and Th17 cytokines profiles. We compared immunological parameters between time points with clinical parameters and as predictors for OS and DFS after SABR.

The median OS and DFS for the entire group were 45.6 (25%-75%: 28.4-78.5) and 35.3 (25-75%: 10.6-60.2) months, respectively. Early (TP2 vs TP1) increase in the percentage of PD-1+ and CTLA4+ cells (CD4+ and CD8+ subtypes) was observed, with a delayed (TP3) increase in the rate of CD8+ lymphocytes expressing CD25 or CD28. The polarization of the immune profile was accompanied by the upregulation of Th1 and Th2 cytokines. The median OS and DFS for the subgroup with an early (TP2) increase in the percentage of PD-1+ and RORγt+ lymphocytes were significantly longer, at 54.1 and 46.5 months, respectively, compared with 32.7 and 13.5 months for the subgroup with a decreased both percentages. Moreover, the delayed increase of interleukin-17a predicts longer OS and DFS after SABR.

We confirmed that SABR stimulates the immune system, which impacts patient clinical outcomes. A simultaneous increase in the percentage of PD-1+ lymphocytes and upregulation of Th17 response after SABR is an independent favorable prognostic factor.