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Granzyme B (GZMB)-Positive Tumor-Infiltrating Lymphocytes in Lung Adenocarcinoma: Significance as a Prognostic Factor and Association with Immunosuppressive Proteins

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Abstract

Background

Granzyme B (GZMB) is a serine protease produced by cytotoxic lymphocytes that reflects the activity of anti-tumor immune responses in tumor-infiltrating lymphocytes (TILs); however, the prognostic significance of GZMB+ TILs in lung adenocarcinoma is poorly understood.

Methods

We analyzed 273 patients with pathological stage (pStage) I–IIIA lung adenocarcinoma who underwent surgery at Kyushu University from 2003 to 2012. We evaluated GZMB+ TIL counts by immunohistochemistry. We set the cut-off values at 12 cells/0.04 mm2 for GZMB+ TILs and divided the patients into GZMB-High (n = 171) and GZMB-Low (n = 102) groups. Then, we compared the clinicopathological characteristics of the two groups and clinical outcomes. Programmed cell death ligand-1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) expression in tumor cells was also evaluated, and combined prognostic analyses of GZMB+ TILs with PD-L1 or IDO1 were performed.

Results

GZMB-Low was significantly associated with pStage II–III, PD-L1 positivity, and IDO1 positivity. Disease-free survival (DFS) and overall survival (OS) in the GZMB-Low group were significantly worse than in the GZMB-High group. In multivariable analysis, GZMB-Low was an independent prognostic factor for both DFS and OS. Furthermore, combined prognostic analyses of GZMB+ TILs with PD-L1 or IDO1 showed that GZMB-Low with high expression of these immunosuppressive proteins had the worst prognosis.

Conclusions

We analyzed GZMB+ TIL counts in lung adenocarcinoma and elucidated its prognostic significance and association with PD-L1 and IDO1. GZMB+ TIL counts might reflect the patient’s immunity against cancer cells and could be a useful prognostic marker of lung adenocarcinoma.

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Acknowledgment

We thank Miki Nakashima and Yuko Kubota for their invaluable help with tissue processing. We also thank H. Nikki March, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

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Authors and Affiliations

  1. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Fumihiko Kinoshita MD, PhD, Shunichi Saito MD, Asato Hashinokuchi MD, Kyoto Matsudo MD, Taichi Nagano MD, Takaki Akamine MD, PhD, Mikihiro Kohno MD, PhD, Tomoyoshi Takenaka MD, PhD & Tomoharu Yoshizumi MD, PhD

  2. Department of Surgery, Saiseikai Fukuoka General Hospital, Fukuoka, Japan

    Kazuki Takada MD, PhD

  3. Department of Thoracic Surgery, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan

    Sho Wakasu MD, PhD

  4. Department of Biostatistics, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan

    Mototsugu Shimokawa PhD

  5. Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Yoshinao Oda MD, PhD

Authors
  1. Fumihiko Kinoshita MD, PhD
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  2. Kazuki Takada MD, PhD
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Correspondence to Tomoyoshi Takenaka MD, PhD.

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Kinoshita, F., Takada, K., Wakasu, S. et al. Granzyme B (GZMB)-Positive Tumor-Infiltrating Lymphocytes in Lung Adenocarcinoma: Significance as a Prognostic Factor and Association with Immunosuppressive Proteins. Ann Surg Oncol 30, 7579–7589 (2023). https://doi.org/10.1245/s10434-023-14085-z

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