Predictive value of TCR Vβ-Jβ profile for adjuvant gefitinib in EGFR mutant NSCLC from ADJUVANT-CTONG 1104 trial

Abstract

Herein, we characterize the landscape and prognostic significance of the T cell receptor (TCR) repertoire of early-stage non–small cell lung cancer (NSCLC) for patients with an epidermal growth factor receptor ( EGFR ) mutation. β Chain TCR sequencing was used to characterize the TCR repertoires of paraffin-preserved pretreatment tumor and tumor-adjacent tissues from 57 and 44 patients with stage II/III NSCLC with an EGFR mutation treated with gefitinib or chemotherapy in the ADJUVANT-CTONG 1104 trial. The TCR diversity was significantly decreased in patients with an EGFR mutation, and patients with high TCR diversity had a favorable overall survival (OS). A total of 10 TCR Vβ-Jβ rearrangements were significantly associated with OS. Patients with a higher frequency of Vβ5-6Jβ2-1, Vβ20-1Jβ2-1, Vβ24-1Jβ2-1, and Vβ29-1Jβ2-7 had significantly longer OS. Weighted combinations of the 4 TCRs were significantly associated with OS and disease-free survival (DFS) of patients, which could further stratify the high and low TCR diversity groups. Importantly, Vβ5-6Jβ2-1, Vβ20-1Jβ2-1, and Vβ24-1Jβ2-1 had a significant relationship with gefitinib treatment, while Vβ29-1Jβ2-7 was associated with chemotherapy. Four TCR Vβ-Jβ rearrangements related to favorable OS and DFS for adjuvant gefitinib and chemotherapy in patients with an EGFR mutation with stage II/III NSCLC; this may provide a novel perspective for the adjuvant setting for resectable NSCLC.

Predictive value of intra‐tumoural TCRβ rearrangements in precisely selecting adjuvant therapy for EGFR‐mutant non‐small‐cell lung cancer

“…We described the positive or negative association of special TCR rearrangements with clinical outcomes and their role for potential guiding adjuvant TKI or chemotherapy decisions in EGFR ‐mutant NSCLC patients (Figure 1). As expected, low TCR repertoire diversity was significantly associated with poor overall survival (OS) in early‐stage NSCLC patients with an EGFR mutation 9 . Of note, we identified four special TCR Vβ‐Jβ rearrangements associated with favourable OS, which may have an anti‐tumour response to NSCLC.…”

Poor prognosis of intra‐tumoural TRBV6‐6 variants in EGFR‐mutant NSCLC: Results from the ADJUVANT‐CTONG1104 trial

“…A total of 356 distinct TCR rearrangements were identified. 8 Notably, Vβ6‐6Jβ1‐3 and Vβ6‐6Jβ1‐6 demonstrated statistical significance in predicting poor overall survival (OS) (FDR adjusted p < .05, Figure 1A ). Importantly, the combination of Vβ6‐6Jβ1‐3 and Vβ6‐6Jβ1‐6 was the best model in predicting OS (Figure 1B ), which was internally validated by 100 repeated 10‐fold cross‐validation (Figure S3) .…”

TCR engineered T cells for solid tumor immunotherapy

“…We also discovered that our previously identified chronic myeloid leukemia (CML)-associated TCR Vβ clone specifically recognizes Wilm’s tumor 1 (WT1) antigenic peptides by stimulating T cells in healthy donors with MHC-restricted antigenic peptides and TCR Vβ gene sequencing [ 26 ]. Recently, our team and partners have also found TCR Vβ clones that are closely related to the prognosis of lung cancer patients [ 27 ]. Our team recently analyzed the TCR Vα and Vβ chain genes of T cells from B cell-acute lymphoid leukemia (B-ALL) patients by single-cell sequencing and found that the patients’ T cells had polyclonal subtypes, and most of them were effector subsets [ 28 ].…”

“…The result of this study contributes to a better understanding of the role of TCR-T cell therapy in NSCLC. In the clinical trial CTONG 1104, our team and partners found that TCR Vβ5–6 Jβ2 − 1, TCR Vβ20 − 1 Jβ2 − 1, and TCR Vβ24 − 1 Jβ2 − 1 in NSCLC patients with an EGFR mutation were associated with good overall survival (OS) in the gefitinib group, while TCR Vβ29 − 1 Jβ2–7 was related to good OS in the conventional chemotherapy group [ 27 ]. These results suggested that TCR-T cells, based on these specific TCRs and combined with existing targeted therapies, may benefit more NSCLC patients.…”

“…Targeting neoantigens produced by tumor gene mutations may be an effective way to reduce the nonspecific cytotoxicity of TCR-T cells. In the clinical trial CTONG 1104 (the 1st generation EGFR-TKI adjuvant gefitinib improves disease-free survival (DFS) for resected EGFR-mutant NSCLC with N1/N2 metastasis), we found that significant TCR rearrangements (Vβ5-6-Jβ2 − 1, Vβ20-1-Jβ2 − 1, Vβ24-1-Jβ2 − 1, and Vβ29-1-Jβ2–7) in NSCLC patients are associated with favorable overall survival (OS) and may have a specific response to tumor gene mutations [ 27 ]. Thus, with the comprehensive application of immunome library sequencing, single-cell sequencing, and MCR engineering report cell technology, obtaining and constructing TCR-T cells targeting neoantigens may be a potential strategy for cancer immunotherapy.…”