TCR Repertoire Diversity of Peripheral PD-1+CD8+ T Cells Predicts Clinical Outcomes after Immunotherapy in Patients with Non–Small Cell Lung Cancer

Abstract

T-cell receptor (TCR)-based biomarkers might predict patient response to immune checkpoint blockade (ICB) but need further exploration and validation for that use. We sequenced complementarity-determining region 3 of TCRb chains isolated from PD-1 þ CD8 þ T cells to investigate its value for predicting the response to anti-programmed cell death 1 (PD-1)/PD-ligand 1 (PD-L1) therapy in patients with non-small cell lung cancer (NSCLC). Two independent patient cohorts (cohort A, n ¼ 25; cohort B, n ¼ 15) were used as discovery and validation sets, respectively. Pre-and post-ICB peripheral blood samples were collected. In cohort A, patients with high PD-1 þ CD8 þ TCR diversity before ICB treatment showed better response to ICB and progression-free survival (PFS) compared with patients with low diversity [6.4 months vs. 2.5 months, HR, 0.39; 95% confidence interval (CI), 0.17-0.94; P ¼ 0.021]. The results were validated in cohort B. Pre-ICB PD-1 þ CD8 þ TCR diversity achieved an optimal Youden's index of 0.81 (sensitivity ¼ 0.87 and specificity ¼ 0.94) for differentiating the ICB response in the merged dataset (cohort A plus cohort B). Patients with increased PD-1 þ CD8 þ TCR clonality after ICB treatment had longer PFS (7.3 months vs. 2.6 months, HR, 0.26; 95% CI, 0.08-0.86; P ¼ 0.002) than those with decreased clonality. Thus, TCR diversity and clonality in peripheral blood PD-1 þ CD8 þ T cells may serve as noninvasive predictors of patient response to ICB and survival outcomes in NSCLC.

Molecular T-Cell Repertoire Analysis as Source of Prognostic and Predictive Biomarkers for Checkpoint Blockade Immunotherapy

“…This interpretation is supported by the dynamics of peripheral PD-1+/CD8+ TCR repertoire during treatment. In fact, the authors found that TCR clonality of sorted PD-1+/CD8+ T cells positively associated with survival outcomes, that is patients with increased clonality had improved survival outcomes as compared to those with decreased TCR clonality [82]. Overall this study point to the PD-1+/CD8+ T cells as source of predictive biomarkers with clinical utility.…”

“…The first conflicting results on the prognostic and predictive significance of peripheral TCR diversity and clonality in metastatic melanoma may be due to the existence in the whole TCR repertoire of a large number of non-tumor specific TCRs that dilute tumor neoantigen specific TCRs. Starting from this assumption, Han J. et al thought to focus on PD-1+/CD8+ exhausted T cells [82], since this cell subset seems to include the highest number of cytotoxic T cells specific for neoantigen [95]. They found that pretreatment TCR diversity of sorted peripheral PD-1+/CD8+ T cells predicted clinical response to anti PD-1/PD-L1 CBI in non-small cell lung cancer (NSCLC), since patients with a higher diversity had a significantly longer progression-free and overall survival than those with lower diversity.…”

Characteristics of TCR Repertoire Associated With Successful Immune Checkpoint Therapy Responses

“…Patients with high pre-treatment TCR diversity, and reduced diversity post anti-PD-1 treatment in their CD8 + PD-1 + T cell population had longer progression-free survival. Importantly, these associations with treatment outcomes were not observed when TCR sequencing was performed on blood CD8 + T cells ( 66 , 68 ).…”

Systemic Blood Immune Cell Populations as Biomarkers for the Outcome of Immune Checkpoint Inhibitor Therapies

“…It was speculated that having a high TCR clonal diversity could correlate with higher probabilities to establish efficacious anti-tumor immune responses. Consequently, several studies have indeed associated a better response to a more diverse TCR repertoire in peripheral T cells [60][61][62][63].…”