Peripheral PD-1⁺CD8⁺ T-cell TCR Dynamics During Radiation Therapy Predict Survival in Unresectable Locally Advanced Non-Small Cell Lung Cancer.

PURPOSE: Immune checkpoint inhibitors (ICIs) have improved outcomes for patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC). However, reliable biomarkers for predicting response to immunotherapy remain limited. Among circulating immune cells, PD-1⁺CD8⁺ T cells represent an activated subset that directly responds to PD-1 blockade. Profiling the T-cell receptor (TCR) repertoire within this population may reflect antitumor immune activity and holds promise as noninvasive, blood-based biomarker.

METHODS AND MATERIALS: We prospectively enrolled 63 patients with unresectable LA-NSCLC who underwent chemoradiation therapy. Peripheral blood PD-1⁺CD8⁺ T cells were isolated from peripheral blood mononuclear cells obtained by density gradient centrifugation at 3 time points: before radiation therapy, during radiation therapy (on-RT, approximately at the 20th fraction), and after radiation therapy (post-RT), yielding a total of 141 blood samples. TCR sequencing was performed to assess repertoire diversity. Dynamic changes in TCR diversity metrics across time points were analyzed and correlated with progression-free survival (PFS).

RESULTS

A higher D50 index on-RT was significantly associated with improved median PFS (not reached vs 21.95 months; P = .0246), regardless of the timing of immunotherapy. Patients with more stable TCR diversity and clonality on-RT experienced significantly longer PFS. Specifically, patients with low D50 index variation between on-RT and post-RT had a median PFS that was not reached (95% CI, 30.72-NA), compared with 21.95 months (95% CI, 17.84-NA; P = .018) in the high-variation group. Similarly, patients with low clonality variation demonstrated longer PFS from pre-RT to on-RT (30.72 vs 21.95 months; P = .0425) and from on-RT to post-RT (not reached vs 22.21 months; P = .0331). Clonal tracking analyses revealed that patients with short-PFS exhibited a higher proportion of markedly decreased TCR clones, particularly among high-frequency clones, suggesting impaired antitumor immune responses.

CONCLUSIONS

Peripheral PD-1⁺CD8⁺ TCR diversity and its dynamic changes on-RT are associated with PFS in patients with LA-NSCLC. These findings suggest that TCR repertoire profiling of circulating PD-1⁺CD8⁺ T cells may serve as a noninvasive biomarker to identify patients less likely to benefit from consolidation immunotherapy. Further validation in larger, prospective cohorts is warranted.