Neuropilin-1 is a valuable biomarker for predicting response of advanced non-small cell lung cancer patients to hypofractionated radiotherapy and PD-1 blockade

•HFRT combined with PD1 blockade improves the outcome of NSCLC.•Elevated expression of NRP1 and TOX on T cells from patients with advanced NSCLC.•Reduced expression of NRP1 and TOX in peripheral CD8+ T cells indicates longer overall survival in NSCLC. Programmed death-1 (PD-1) blockade promoted the combination therapy of advanced non-small cell lung cancer (NSCLC), induces changes in peripheral memory T cell subsets. Neuropilin-1 (NRP1) is a new T cell memory checkpoint, its association with the clinical prognosis of NSCLC is less reported. Here, we detected the expression of NRP1 and the depletion-associated factor thymocyte selection-associated HMG box protein (TOX) in peripheral T cell subsets with responders treated with hypofractionated radiotherapy (HFRT) combined with PD-1 blockade and chemoimmunotherapy, aimed to explore their association with the prognosis of advanced NSCLC. NRP1 and TOX expression was localized on tissue-infiltrating T cells by immunofluorescence assay in nine patients who had undergone surgery. Flow cytometry was used to detect the expression of NRP1 and TOX in peripheral circulating T cells in patients with advanced NSCLC before and after HFRT combined with PD-1 blockade (HFRT+PD-1) and chemoimmunotherapy in thirty-nine patients. NSCLC patients showed an increase in NRP1 and TOX in peripheral T cells as compared to that in healthy controls. The expression of NRP1 and TOX in CD8+ T cells was higher in tumor tissues than in uninvolved tissues. Patients who responded to HFRT+PD-1 blockade showed a reduction in NRP1+CD8+, TOX+CD4+, and TOX+CD8+ levels, chemoimmunotherapy responders showed decreased expression of NRP1 in the CD4+ T cell subpopulation. In conclusion, lower expression levels of NRP1 and TOX in peripheral circulating CD8+ T cells were associated with a better prognosis for advanced NSCLC patients treated with HFRT+PD-1 blockade.