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Prognostic value and clinicopathological roles of the tumor immune microenvironment in salivary duct carcinoma

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Abstract

Salivary duct carcinoma (SDC) is an aggressive type of salivary gland carcinoma. Recently, immunotherapies targeting immune checkpoints, including PD1, PD-L1, CTLA4, and LAG3, have had a considerable prognostic impact on various malignant tumors. The implementation of such immune checkpoint inhibitor (ICI) therapies has also been attempted in cases of salivary gland carcinoma. The tumor immune microenvironment (TIME) is implicated in tumorigenesis and tumor progression and is closely associated with the response to ICI therapies. However, the TIME in SDC has not been fully explored. We examined the immunohistochemical expression of CD8, FOXP3, PD1, PD-L1, CTLA4, LAG3, and mismatch repair (MMR) proteins, tumor-infiltrating lymphocytes (TILs), and microsatellite instability (MSI) status in 175 cases of SDC. The associations between these TIME-related markers and the clinicopathological factors and prognosis were evaluated. An elevated expression of CD8, FOXP3, PD1, CTLA4, and LAG3 was associated with more aggressive histological features and an advanced N and/or M classification, elevated Ki-67 index, and poor prognosis. Furthermore, cases with a high PD-L1 expression exhibited more aggressive histological features and adverse clinical outcomes than those with a low expression. Alternatively, there was no significant correlation between TILs and clinicopathological factors. No SDC cases with an MSI-high status or MMR deficiency were found. The coexistence of both an immunostimulatory and immunosuppressive TIME in aggressive SDC might play a role in the presence of T-cell exhaustion. The contribution of multiple immune escape pathways, including regulatory T cells and immune checkpoints, may provide a rationale for ICI therapy, including combined PD1/CTLA4 blockade therapy.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by Tokyo Medical University Research Grant to N. Saigusa and JSPS Grant-in-Aid for Scientific Research (C) to Y. Tada (no.21K09616), T. Nagao (no. 20K07417, 23K06432), T. Matsuki (no. 20K07597) and M. Nakaguro (no. 22K06939) and a Grant-in-Aid for Young Scientists to H. Hirai (no. 19K165681, 22K06969) and C. Fushimi (no. 21K16835). The authors thank M. Yokotsuka for performing the gene mutation analysis and Y. Yamamoto and H. Yokota for performing the immunohistochemical analysis.

Author information

Author notes

  1. Hideaki Hirai, Masato Nakaguro, Yuichiro Tada and Natsuki Saigusa are contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Department of Anatomic Pathology, Tokyo Medical University, 6-7-1 Nishi-Shinjuku, Shinjuku-Ku, Tokyo, 160-0023, Japan

    Hideaki Hirai, Natsuki Saigusa, Manami Kajiwara, Yoshitaka Utsumi & Toshitaka Nagao

  2. Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan

    Masato Nakaguro

  3. Department of Head and Neck Oncology and Surgery, International University of Health and Welfare, Mita Hospital, Tokyo, Japan

    Yuichiro Tada & Chihiro Fushimi

  4. Dental and Maxillofacial Radiology and Oral Pathology Diagnostic Services, The Nippon Dental University Hospital, Tokyo, Japan

    Natsuki Saigusa

  5. Department of Otorhinolaryngology, Head and Neck Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    Daisuke Kawakita

  6. Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan

    Yoshitaka Honma

  7. Department of Otolaryngology Head and Neck Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan

    Satoshi Kano

  8. Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University, Tokyo, Japan

    Kiyoaki Tsukahara & Akira Shimizu

  9. Department of Otorhinolaryngology Head and Neck Surgery, Keio University School of Medicine, Tokyo, Japan

    Hiroyuki Ozawa

  10. Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University Hachioji Medical Center, Hachioji, Japan

    Takuro Okada & Takahito Kondo

  11. Department of Otolaryngology Head and Neck Surgery, Tokai University School of Medicine, Isehara, Japan

    Kenji Okami & Akihiro Sakai

  12. Department of Head and Neck Surgery, Niigata Cancer Center Hospital, Niigata, Japan

    Keisuke Yamazaki, Yuichiro Sato & Takafumi Togashi

  13. Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

    Yukiko Sato

  14. Department of Diagnostic Pathology, Fujita Health University Bantane Hospital, Nagoya, Japan

    Makoto Urano

  15. Department of Otolaryngology, Showa University Fujigaoka Hospital, Yokohama, Japan

    Tomotaka Shimura

  16. Department of Otorhinolaryngology, Head and Neck Surgery, International University of Health and Welfare, Narita Hospital, Narita, Japan

    Yorihisa Imanishi

  17. Department of Otolaryngology, Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan

    Toyoyuki Hanazawa

  18. Department of Otorhinolaryngology, Head and Neck Surgery, Kitasato University School of Medicine, Sagamihara, Japan

    Takashi Matsuki

  19. Department of Surgical Pathology, Teikyo University, Chiba Medical Center, Ichihara, Japan

    Kazuto Yamazaki

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  1. Hideaki Hirai
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Contributions

All authors read and approved the final manuscript. The conception and design of the work, data acquisition, analysis, drafting the manuscript were performed by HH, MN, YT, NS, and TN. Material preparation and data collection were performed by all the authors. HH, MN, YT, NS, DK and TN preformed statistical analysis. YT, DK, YH and TN critically revised the manuscript.

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Correspondence to Toshitaka Nagao.

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Hirai, H., Nakaguro, M., Tada, Y. et al. Prognostic value and clinicopathological roles of the tumor immune microenvironment in salivary duct carcinoma. Virchows Arch 483, 367–379 (2023). https://doi.org/10.1007/s00428-023-03598-3

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