Circulating CD28-KLRG1+CD8+ T cells involve in systemic and local immunity that predicts chemoimmunotherapy outcomes in advanced NSCLC.

BACKGROUND

Chemoimmunotherapy has become the standard first-line treatment for advanced non-small cell lung cancer (NSCLC). Deciphering the T-cell subset responsible for chemoimmunotherapy and easily tested conveniently is critical in predicting the treatment outcomes.

METHODS

Based on peripheral blood collected from patients enrolled from a phase 2 clinical study (ClinicalTrials.gov NCT04836728), we performed multi-color flow cytometry and unsupervised analysis to explore correlations with therapeutic outcomes. We integrated single-cell RNA and T-cell receptor (TCR) sequencing in 36 samples, including peripheral blood, tumors and non-tumor tissues, from 8 NSCLC patients to interpret the correlation, which was further verified using blood samples, orthotopic and subcutaneous lung cancer mouse model.

RESULTS

The baseline CD28-KLRG1+CD57+ and on-treatment CD28-KLRG1+ CD8+ T cells in peripheral blood were independent factors which indicated improved treatment outcomes in advanced NSCLC patients receiving first-line chemoimmunotherapy. While being in a late-differentiated T-cell status, these cells were clonally expanded and reinvigorated during chemoimmunotherapy, serving as a peripheral T-cell pool for supplying potential tumor-reactive T cells in tumors, and reversely differentiating into less-differentiated subsets. The zinc-metallothionein pathway regulated the CD28-KLRG1+ CD8+ T-cell subset. Zinc supplementation combined with chemoimmunotherapy improved both local and systemic antitumor immune responses in mouse model.

CONCLUSIONS

Circulating CD28-KLRG1+ CD8+ T cells are valuable and convenient biomarkers for first-line chemoimmunotherapy in advanced NSCLC and provide insight into how late-differentiated or senescent T cells engage in the antitumor immunity when immunotherapy is added to conventional therapies.