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. 2023 Feb 28;12(2):257-265.
doi: 10.21037/tlcr-22-666. Epub 2023 Feb 21.

Peripheral T-cell receptor repertoire dynamics in small cell lung cancer

Meridith L Balbach  1   2 , Margaret L Axelrod  1   2 , Justin M Balko  2   3 , Armand Bankhead  4 , Tristan Shaffer  4 , Lee Lim  4 , Jiannan Guo  4 , Jennifer Hernandez  4 , Mark Li  4 , Wade T Iams  2   3
Affiliations

Peripheral T-cell receptor repertoire dynamics in small cell lung cancer

Meridith L Balbach et al. Transl Lung Cancer Res. .

Abstract

Background: Identifying a circulating biomarker predictive of immune checkpoint inhibitor (ICI) benefit in patients with small cell lung cancer (SCLC) remains an unmet need. Characteristics of peripheral and intratumoral T-cell receptor (TCR) repertoires have been shown to predict clinical outcomes in non-small cell lung cancer (NSCLC). Recognizing a knowledge gap, we sought to characterize circulating TCR repertoires and their relationship with clinical outcomes in SCLC.

Methods: SCLC patients with limited (n=4) and extensive (n=10) stage disease were prospectively enrolled for blood collection and chart review. Targeted next-generation sequencing of TCR beta and alpha chains of peripheral blood samples was performed. Unique TCR clonotypes were defined by identical CDR3, V gene, and J gene nucleotide sequences of the beta chain and subsequently used to calculate TCR diversity indices.

Results: Patients with stable versus progressive and limited versus extensive stage disease did not demonstrate significant differences in V gene usage. Kaplan-Meier curve and log-rank analysis did not identify a statistical difference in progression-free survival (PFS) (P=0.900) or overall survival (OS) (P=0.200) between high and low on-treatment TCR diversity groups, although the high diversity group exhibited a trend toward increased OS.

Conclusions: We report the second study investigating peripheral TCR repertoire diversity in SCLC. With a limited sample size, no statistically significant associations between peripheral TCR diversity and clinical outcomes were observed, though further study is warranted.

Keywords: T-cell receptor (TCR); T-cell receptor repertoire (TCR repertoire); biomarker; immunogenomics; small cell lung cancer (SCLC).

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-666/coif). MLA is listed as a coinventor on a provisional patent application for methods to predict therapeutic outcomes using blood-based gene expression patterns, that is owned by Vanderbilt University Medical Center, and is currently unlicensed. JMB receives research support from Genentech/Roche, Bristol Myers Squibb, and Incyte Corporation, has received consulting/expert witness fees from Novartis, and is an inventor on patents regarding immunotherapy targets and biomarkers in cancer. AB, TS, LL, JG, JH, and ML are current or former employees of Resolution Bioscience, a part of Agilent. WTI has served as a consultant for Bristol Myers Squibb, OncLive, Clinical Care Options, Chardan, Outcomes Insights, Cello Health, and Curio Science. He reports advisory board participation for Genentech, Jazz Pharma, G1 Therapeutics, Mirati, and Takeda. The other authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Samples derived from patients with variable disease characteristics demonstrate similar V gene usage frequencies. (A) Pooled gene usage frequencies in patients with SD (blue) versus PD (red) did not demonstrate significant differences in 45 V genes of the beta chain, with points representing individual gene frequencies (n=41). (B) Similarly, poled gene usage frequencies in patients with limited (red) versus progressive (blue) disease did not demonstrate significant differences in 45 V genes of the beta chain (n=41). PD, progressive disease; SD, stable disease; TRBV, T-cell receptor beta variable gene.
Figure 2
Figure 2
Patients with stable and progressive disease exhibit similar TCR repertoire diversity. (A) Comparison of TCR diversity in first available samples derived from patients with SD versus PD did not demonstrate a significant difference (P=0.351, n=14). (B) TCR repertoire diversity derived from Shannon Index for all samples with corresponding clinical response, SD (blue) or PD (red). TCR, T cell receptor; PD, progressive disease; SD, stable disease.
Figure 3
Figure 3
Clinical outcomes stratified by high and low TCR diversity. ROC analysis identified TCR diversity as a poor predictor of PFS (A) but a good predictor of OS (B), with an AUC of 0.89 and optimal Shannon diversity threshold of 7.7821 per Youden index analysis (n=6). (C) Using this threshold, TCR diversity was used to classify patients into high (n=3) and low (n=3) diversity subsets, finding no statistical difference (P=0.90) in PFS between the two groups. (D) Although differences in OS were insignificant (P=0.20), the high diversity group exhibited a trend toward improved OS. TCR, T cell receptor; PFS, progression-free survival; OS, overall survival; AUC, area under the curve; ROC, receiver operating characteristic.
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References

    1. Gay CM, Stewart CA, Park EM, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell 2021;39:346-360.e7. 10.1016/j.ccell.2020.12.014 - DOI - PMC - PubMed
    1. Iams WT, Porter J, Horn L. Immunotherapeutic approaches for small-cell lung cancer. Nat Rev Clin Oncol 2020;17:300-12. 10.1038/s41571-019-0316-z - DOI - PMC - PubMed
    1. Nixon AB, Schalper KA, Jacobs I, et al. Peripheral immune-based biomarkers in cancer immunotherapy: can we realize their predictive potential? J Immunother Cancer 2019;7:325. 10.1186/s40425-019-0799-2 - DOI - PMC - PubMed
    1. Okła K, Farber DL, Zou W. Tissue-resident memory T cells in tumor immunity and immunotherapy. J Exp Med 2021;218:e20201605. 10.1084/jem.20201605 - DOI - PMC - PubMed
    1. Reuben A, Zhang J, Chiou SH, et al. Comprehensive T cell repertoire characterization of non-small cell lung cancer. Nat Commun 2020;11:603. 10.1038/s41467-019-14273-0 - DOI - PMC - PubMed