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Definitive chemoradiotherapy induces T-cell-inflamed tumor microenvironment in unresectable locally advanced esophageal squamous cell carcinoma

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Abstract

Background

Chemoradiotherapy (CRT) modulates the tumor immune microenvironment of multiple cancer types, including esophageal cancer, which potentially induces both immunogenicity and immunosuppression by upregulating the presentation of tumor-specific antigens and immune checkpoint molecules in tumors, respectively. The prognostic effects of immune modification by CRT in esophageal squamous cell carcinoma (ESCC) remain controversial because of the lack of detailed immunological analyses using paired clinical specimens before and after CRT. We aimed to clarify the immunological changes in the tumor microenvironment caused by CRT and elucidate the predictive importance of clinical response and prognosis and the rationale for the necessity of subsequent programmed cell death protein 1 (PD-1) inhibitor treatment.

Methods

In this study, we performed a comprehensive immunological analysis of paired biopsy specimens using multiplex immunohistochemistry before and after CRT in patients with unresectable locally advanced ESCC.

Results

CRT significantly increased the intra-tumoral infiltration and PD-1 expression of CD8+ T cells and conventional CD4+ T cells but decreased those of regulatory T cells and the accumulation of tumor-associated macrophages. Multivariate analysis of tumor-infiltrating T-cell phenotypes revealed that the density of PD-1+CD8+ T cells in the tumor after CRT could predict a confirmed complete response and favorable survival.

Conclusions

This study showed that CRT improved the immunological characteristics of unresectable locally advanced ESCC and identified the density of PD-1+CD8+ T cells as a predictive factor for prognosis. This finding supports the rationale for the necessity of subsequent PD-1 inhibitor treatment.

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Acknowledgements

We thank all patients who participated in this study and their families and caregivers. We thank T. Takaku, K. Onagawa, M. Takemura, M. Hoshino, Y. Osada, C. Ozawa, and X. Takakura for their technical assistance.

Funding

This study was supported by a Grant-in-Aid for Scientific Research (C Grant No. 21K07252 [S. Koyama], JSPS Fellows no. 22KJ3156 [S. Kumagai], Early-Career Scientists no. 23K15088 [S. Kumagai], PAGS nos. 202130, 212126, 221184, and 231279 [S. Kumagai]); Japan Agency for Medical Research and Development (AMED)—the Moonshot Research and Development Program grant (no. 22zf0127009h0001 [H. Nishikawa, S. Koyama]); AMED—the Project for Promotion of Cancer Research and Therapeutic Evolution (P-PROMOTE no. 22ama221301h0001 [H. Nishikawa, S. Koyama.], no. 22ama221507h0001 [S. Kumagai], no. 23ama221329h0001 [S.Koyama]); AMED—the Practical Research for Innovative Cancer Control (no. 22ck0106724h0001 [H. Nishikawa, S. Koyama], no.22ck0106773h0001 [S. Kumagai], no. 23ck0106796h0001 [S. Koyama]); Canon Foundation (S. Koyama.); Mitsubishi Foundation (S. Koyama.); Takeda Science Foundation (S. Kumagai); Taiju Life Social Welfare Foundation (S. Kumagai); Astellas Foundation for Research on Metabolic Disorders (S. Kumagai); Senri Life Science Foundation (S. Kumagai); Uehara Memorial Foundation (S. Kumagai); Chugai Foundation for Innovative Drug Discovery Science (S. Kumagai); Japan Neurosurgical Society (S. Kumagai); and Japan Lung Cancer Society (a nonprofit organization) (S. Kumagai).

Author information

Author notes

  1. Takumi Habu and Shogo Kumagai are contributed equally to this study.

Authors and Affiliations

  1. Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Kashiwa, Chiba, Japan

    Takumi Habu, Shogo Kumagai, Hiroyoshi Nishikawa & Shohei Koyama

  2. Department of Gastric Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

    Takumi Habu & Takahiro Kinoshita

  3. Course of Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine, Tokyo, Japan

    Takumi Habu & Shuichi Mitsunaga

  4. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

    Hideaki Bando, Saori Mishima, Daisuke Kotani & Takashi Kojima

  5. Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

    Takeshi Fujisawa, Masaki Nakamura, Hidehiro Hojo & Takashi Kojima

  6. Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan

    Shingo Sakashita

  7. Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, Kashiwa, Chiba, Japan

    Tomonori Yano

  8. Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    Shohei Koyama

  9. Division of Biomarker Discovery, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan

    Shuichi Mitsunaga

  10. Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Hiroyoshi Nishikawa

Authors
  1. Takumi Habu
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  2. Shogo Kumagai
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Contributions

T. Habu, S. Kumagai, H. Bando, S. Koyama, and T. Kojima designed the study. T. Habu, S. Kumagai, and S. Koyama wrote the initial draft of the manuscript. T. Habu, S. Kumagai, H. Bando, S. Koyama, and T. Kojima contributed to the analysis and interpretation of the data and assisted in manuscript preparation. All the other authors contributed to the data collection, interpretation, and critical review of the manuscript. All authors have approved the final version of the manuscript and agreed to be accountable for all aspects of the study. We ensured that all questions related to the accuracy or integrity of any part of the study were appropriately investigated and resolved.

Corresponding authors

Correspondence to Shohei Koyama or Takashi Kojima.

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Conflict of interest

H. Bando reports honoraria from Ono Pharmaceutical, Taiho Pharmaceutical and Eli Lilly Japan. D. Kotani reports honoraria from Takeda, Chugai, Lilly, MSD, Ono, Seagen, Guardant Health, Eisai, Taiho, Bristol Myers Squibb, Daiichi-Sankyo, Pfizer, Merckbiopharma, and Sysmex, research funding from Ono, MSD, Novartis, Servier, Janssen, IQVIA, Syneoshealth, CIMIC, and Cimicshiftzero. M. Nakamura reports receiving personal fees from AstraZeneca and a research grant from illumina, outside the submitted work. S. Mitsunaga reports honoraria and research funding from Toray Industries, Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co., Ltd., Astellas Pharma, A**omoto, Taiho Pharmaceutical Co., Ltd., PFDeNA outside the submitted work, and personal fees from Ono Pharmaceutical Co. Ltd. outside the submitted work. H. Nishikawa received research funding and honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, and MSD, honoraria from Amgen and research funding from Taiho Pharmaceutical, Daiichi-Sankyo, Kyowa Kirin, Zenyaku Kogyo, Oncolys BioPharma, Debiopharma, Asahi-Kasei, Sysmex, Fujifilm, SRL, Astellas Pharmaceutical, Sumitomo Dainippon Pharma, and BD Japan outside of this study. S. Koyama has received research funding from Otsuka Pharmaceutical and Chugai Pharmaceuticals. T. Kojima reports receiving research funding from Beigene Ltd., AstraZeneca, Chugai Pharmaceutical, Parexel International, Shionogi, Taiho Pharmaceutical, Astellas Amgen BioPharma, MSD, and Ono Pharmaceutical; honoraria from Ono Pharmaceutical, Covidien Japan, MSD, Boehringer Ingelheim, Kyowa Kirin, EA Pharma, Bristol-Myers Squibb, 3H Clinical Trial, AstraZeneca, Taiho Pharmaceutical, Liang Yi Hui Healthcare Oncology News China, Japanese Society of Pharmaceutical Health Care and Sciences, Oncolys BioPharma, and BMS; advisory roles for Ono Pharmaceutical, Taiho Pharmaceutical, Japanese Society of Pharmaceutical Health Care and Sciences, and Liang Yi Hui Healthcare Oncology News China. All other authors have no conflicts of interest to disclose.

Ethical approval

The study protocol was approved by the Institutional Review Board of the National Cancer Center (2021–2022). This study was conducted in accordance with the Declaration of Helsinki and the Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects.

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Supplementary Information

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Supplementary file1 (DOCX 18 KB)

Online Resource 2

The effects of CRT on immune checkpoint molecules expressed by TIL subpopulations. We evaluated the changes in immune checkpoint molecule expression induced by TILs before and after CRT. The densities of each TIL subpopulation before and after CRT were compared using a paired t test. a Programmed cell death protein 1 positivity in CD3+, CD3+CD8+, CD3+CD8–FoxP3–, and CD3+CD8–FoxP3+ lymphocytes before and after CRT. b The densities of CD3+CD8+TIGIT+ (left), CD3+CD8+LAG-3+ (middle), and CD3+CD8+Tim-3+ (right) cells in the tumor bed before and after CRT. c The densities of CD3+CD8–FoxP3+CTLA-4+ lymphocytes before and after CRT. (DOCX 904 KB)

Online Resource 3

The association between TIL phenotypes before CRT and cCR. The densities of the TIL subpopulations before CRT were compared between patients who experienced cCR and those who did not. a The densities of CD3+ (left), CD3+CD8+ (middle), and CD3+CD8–Foxp3– (right) lymphocytes before CRT were compared between the two groups. b The densities of CD3+CD8–Foxp3+ lymphocytes (left) and CD206+ macrophages (right) before CRT were compared between the two groups. c The densities of CD3+PD-1+, CD3+CD8+PD-1+, CD3+CD8–Foxp3−PD-1+, and CD3+CD8–Foxp3+PD-1+ lymphocytes before CRT were compared between the two groups. (DOCX 2214 KB)

Online Resource 4

The association between TIL phenotypes before CRT and PFS. The PFS of patients with esophageal squamous cell carcinoma was evaluated according to TIL phenotypes before CRT using the Kaplan–Meier analysis. The PFS curves of patients are shown, according to the densities of CD3+ (a), CD3+PD-1+ (b), CD3+CD8+ (c), CD3+CD8+PD-1+ (d), CD3+CD8–Foxp3– (e), CD3+CD8–Foxp3–PD-1+ (f), and CD3+CD8–Foxp3+ lymphocytes (g) and CD206+ macrophages (h) in the tumor bed before CRT. (DOCX 834 KB)

Online Resource 5.

The effects of CRT on immune checkpoint molecules expressed by TIL subpopulations in non-cCR patients were evaluated. We assessed the changes in immune checkpoint molecule expression induced by TILs before and after CRT in non-cCR patients (n = 27). The densities of each TIL subpopulation before and after CRT were compared using a paired t test. Programmed cell death protein 1 positivity in CD3+, CD3+CD8+, CD3+CD8–FoxP3–, and CD3+CD8–FoxP3+ lymphocytes before and after CRT were examined. (PDF 246 KB)

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Habu, T., Kumagai, S., Bando, H. et al. Definitive chemoradiotherapy induces T-cell-inflamed tumor microenvironment in unresectable locally advanced esophageal squamous cell carcinoma. J Gastroenterol (2024). https://doi.org/10.1007/s00535-024-02120-z

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