Pretreatment Tissue TCR Repertoire Evenness Is Associated with Complete Pathologic Response in Patients with NSCLC Receiving Neoadjuvant Chemoimmunotherapy

Abstract

Characterization of the T-cell receptor (TCR) repertoire may be a promising source for predictive biomarkers of pathological response to immunotherapy in locally-advanced nonsmall cell lung cancer (NSCLC).Experimental Design: In this study, next-generation TCR sequencing was performed in peripheral blood and tissue samples of 40 NSCLC patients, before and after neoadjuvant chemoimmunotherapy (NADIM clinical trial, NCT03081689), considering their complete pathologic response (CPR) or non-CPR. Beyond TCR metrics, tissue clones were ranked by their frequency and spatiotemporal evolution of top 1% clones was determined. Results:We have found a positive association between an uneven TCR repertoire in tissue samples at diagnosis and CPR at surgery. Moreover, TCR most frequent-ranked clones (top 1%) present in diagnostic biopsies occupied greater frequency in the total clonal space of CPR patients, achieving an AUC ROC to identify CPR patients of 0.967 (95% CI, 0.897 to 1.000; p=0.001), and improving the results of PD-L1 TPS (AUC 0.767; p=0.026) or TMB (AUC 0.550; p=0.687). Furthermore, tumors with high pre-treatment top 1% clonal space showed similar immune cell populations but a higher immune reactive gene expression profile. Finally, the selective expansion of pre-treatment tissue top 1% clones in peripheral blood of CPR patients suggests also a peripheral immunosurveillance, which could explain the high survival rate of these patients. Conclusions:We have identified two parameters derived from TCR repertoire analysis that could outperform PD-L1 TPS and TMB as predictive biomarkers of CPR after neoadjuvant chemoimmunotherapy, and unraveled possible mechanisms of CPR involving enhanced tumor immunogenicity and peripheral immunosurveillance.Research.

Revealing Clonal Responses of Tumor-Reactive T-Cells Through T Cell Receptor Repertoire Analysis

“…In addition, responders for PD-1 blockade therapy showed a higher total frequency of blood-tumor overlapping clones in the blood before treatment (44), a greater number of blood-tumor overlapping clones after treatment (32), and more pronounced expansion of blood-tumor overlapping clones in the blood after treatment (45). Similar observations were reported for neoadjuvant chemoimmunotherapy (28) and clinical trial of a humanized anti-CD4 antibody (46,48). The association between the blood-tumor overlapping repertoire in the tumor and clinical responses has also been analyzed.…”

“…A clinical study on anti-PD-1 antibody therapy in melanoma patients showed that the clonality of the TCR repertoire in the tumor before treatment was higher in responders than in nonresponders (23)(24)(25)(26). Similarly, the total frequency of the top 1% clones in tumor repertoire was greater in responders than in non-responders in studies on neoadjuvant immunotherapy in patients with non-small cell lung cancer (NSCLC) (27,28). Furthermore, responders showed more T-cell clones with increased frequency (23) and increased clonality of the T-cell repertoire (29) in the tumor after treatment.…”

A multispecies framework for modeling adaptive immunity and immunotherapy in cancer

“…Responders also had more stable pools of nonspecific stimulus during treatment (Figure 6C). These findings support the notion that prognoses are most favorable when ICB induces focused, oligoclonal responses against highly clonal neoantigens, at least for certain tumor types [21], [40].…”

Pathological Response and Immune Biomarker Assessment in Non-Small-Cell Lung Carcinoma Receiving Neoadjuvant Immune Checkpoint Inhibitors

“…In this study, the clonal space in the peripheral blood of the top 1% of clones in pretreatment tissue samples was significantly reduced in patients with cPR, and no significant reductions were observed in patients without cPR. Interestingly, comparing the immune gene expression profile of pretreatment samples from patients with a high and low top 1% clonal space, several immune gene signatures such as Interferon gamma and IL2 were differentially expressed, suggesting that this biomarker can be used to predict response to therapy and to evaluate tumor immunogenicity [ 94 ].…”