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Clinical significance of peripheral TCR and BCR repertoire diversity in EGFR/ALK wild-type NSCLC treated with anti-PD-1 antibody

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Abstract

Introduction

TCR and BCR repertoire diversity plays a critical role in tumor immunity. Thus, analysis of TCR and BCR repertoires might help predict the clinical efficacy of anti-PD-1 treatment.

Methods

Blood samples from 30 patients with non-small cell lung cancer (NSCLC) treated with anti-PD-1 antibody were collected before and six weeks after treatment initiation. The clinical significance of TCR and BCR repertoire diversity in peripheral blood was evaluated in all the enrolled patients (n = 30) or in the subset with (n = 10) or without (n = 20) EGFR/ALK mutation.

Results

TCR and BCR diversity was significantly correlated at baseline (R = 0.65; P = 1.6 × 10–4) and on treatment (R = 0.72; P = 1.2 × 10–5). Compared to non-responders (SD or PD), responders (PR) showed significantly decreased TCR and BCR diversity after treatment in the EGFR/ALK wild-type subset (P = 0.0014 and P = 0.034, respectively), but not in all the enrolled patients. The post-treatment reduction in TCR and BCR repertoire diversity was also significantly associated with the occurrence of adverse events in the EGFR/ALK wild-type subset (P = 0.022 and P = 0.014, respectively). Patients with more reduced TCR diversity showed better progression-free survival (PFS) in the EGFR/ALK wild-type subset (P = 0.011) but not in the mutant subset.

Conclusions

These findings suggest the clinical significance of changes in peripheral TCR and BCR repertoire diversity after anti-PD-1 treatment in patients with NSCLC without EGFR/ALK mutation. Monitoring of the peripheral TCR and BCR repertoires may serve as a surrogate marker for the early detection of EGFR/ALK wild-type NSCLC patients who would benefit from anti-PD-1 treatment.

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Abbreviations

AE:

Adverse event

ALK:

Anaplastic lymphoma kinase

BCR:

B cell receptor

CT:

Computed tomography

ICI:

Immune checkpoint inhibitor

InvSimp index:

Inverse Simpson's index

NSCLC:

Non-small cell lung cancer

PBMCs:

Peripheral blood mononuclear cells

PD:

Progressive disease

PD-1:

Programmed cell death protein 1

PFS:

Progression-free survival

PR:

Partial response

RG:

Repertoire Genesis

SD:

Stable disease

S–W index:

Shannon–Weaver index

TLS:

Tertiary lymphoid structures

TCR:

T cell receptor

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Acknowledgements

We would like to thank Junya Otake (Kanagawa Cancer Center Research Institute) for sample handling and data acquisition.

Funding

This study was supported by AMED under Grant Number JP20ae0101076 (TS, KA, HS, KY) and JSPS KAKENHI Grant Number JP18K19490 (TS).

Author information

Author notes

  1. Yoshiro Nakahara, Takaji Matsutani, Yuka Igarashi and Norikazu Matsuo have contributed equally to this work.

Authors and Affiliations

  1. Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan

    Yoshiro Nakahara, Haruhiro Saito & Kouzo Yamada

  2. Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan

    Yoshiro Nakahara

  3. Repertoire Genesis, Inc, Ibaraki, Osaka, Japan

    Takaji Matsutani

  4. Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan

    Yuka Igarashi, Hidetomo Himuro & Tetsuro Sasada

  5. Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center Research Institute, Yokohama, Kanagawa, Japan

    Hidetomo Himuro & Tetsuro Sasada

  6. Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan

    Norikazu Matsuo, Tomoaki Hoshino & Koichi Azuma

  7. Biostatistics Center, Kurume University, Kurume, Fukuoka, Japan

    Kenta Murotani

Authors
  1. Yoshiro Nakahara
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Contributions

KA and TS designed the study. HS, KY, KA and TS obtained financial support for this study. YN, YI and HH contributed to data acquisition. NM, TH and KA collected patient samples and completed the follow-up. YN, TM, YI and KM conducted statistical analyses. YN, TM, YI, NM, HS, KY, KM, KA and TS analyzed and interpreted the data. YN, TM and TS wrote the manuscript, and NM and KA provided critical revisions of the manuscript. All authors approved the final version of the manuscript. YN, TM, YI and NM contributed equally as first authors.

Corresponding author

Correspondence to Tetsuro Sasada.

Ethics declarations

Conflicts of interest

TM is an employee of Repertoire Genesis, Inc. YN has received personal fees from MSD, Ono, Chugai, Eli Lilly, Bristol-Myers Squibb and Nippon Boehringer Ingelheim, and grants from Takeda, Bristol-Myers Squibb and Eli Lilly. HS has received personal fees from Ono, Nippon Boehringer Ingelheim and Novartis, and grants from Chugai, AstraZeneca and MSD. KY has received personal fees from Ono, Chugai and Bristol-Myers Squibb. KA has received grants and personal fees from AstraZeneca, MSD, Bristol Myers Squibb, Ono and Chugai. TS has received grants from BrightPath Biotherapeutics. The other authors have declared that no conflict of interest exists.

Ethics approval and consent to participate

The Institutional Review Board of Kurume University approved the study protocol (Approval number: Kurume University 15210). Written informed consent was received from all participants prior to inclusion in the study.

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Not applicable.

Availability of data and material

The datasets used and analyzed during the current study are available on reasonable request.

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Nakahara, Y., Matsutani, T., Igarashi, Y. et al. Clinical significance of peripheral TCR and BCR repertoire diversity in EGFR/ALK wild-type NSCLC treated with anti-PD-1 antibody. Cancer Immunol Immunother 70, 2881–2892 (2021). https://doi.org/10.1007/s00262-021-02900-z

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