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High Stromal TGFBI in Lung Cancer and Intratumoral CD8-Positive T Cells were Associated with Poor Prognosis and Therapeutic Resistance to Immune Checkpoint Inhibitors

  • Translational Research and Biomarkers
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Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

We investigated whether the expression of transforming growth factor-beta-induced protein (TGFBI) and intratumoral immune cells including CD8- and Forkhead box protein P3 (Foxp3)-positive T cells in clinical lung cancer patients could predict the therapeutic response to nivolumab.

Methods

Thirty-three patients who were treated with nivolumab were enrolled in this study. Immunohistochemical analyses of TGFBI, PD-L1, CD8, Foxp3, and vimentin expression were conducted. Serum concentrations of TGFBI and transforming growth factor-beta1 (TGF-β1) were determined by enzyme-linked immunosorbent assay (ELISA).

Results

Cancer TGFBI was not associated with prognosis and therapeutic response to nivolumab, but cancer stromal TGFBI and intratumoral CD8-positive T cells were associated with them. Therefore, we evaluated cancer stromal TGFBI and intratumoral CD8-positive T cells. The high-TGFBI-expression group had poorer clinical responses than did the low-TGFBI-expression group (p < 0.0001). The number of times nivolumab was administered in the high-CD8-expression group was significantly higher than that in the low-CD8-expression group (p = 0.0046). The high-CD8-expression group had better clinical responses than did the low-CD8-expression group (p = 0.0013). Interestingly, all patients in the high-TGFBI/low-CD8-expression group had progressive disease (PD). In contrast, all patients in the low-TGFBI/high-CD8-expression group had PR + SD (partial response + stable disease) by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1).

Conclusions

The dual evaluation of stromal TGFBI and intratumoral CD8-positive T cells could be a useful predictive marker for nivolumab.

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Acknowledgment

The authors thank Ms. Yukie Saito, Ms. Sayaka Okada, Ms. Kayoko Takahashi, Ms. Mizue Murata, Ms. Harumi Kanai, Ms. Fumie Takada, Ms. Sawa Nagayama, and Ms. Mariko Nakamura for their excellent assistance. This work was supported by the research grant from Ono Pharmaceutical Co., Ltd. and Bristol-Myers Squibb K.K and Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS), grant numbers 17K19893, 18K07665, and 18H02877. The work also was supported in part by a Research Grant of the Princess Takamatsu Cancer Research Fund, the Suzuken Memorial Foundation, and the Pancreas Research Foundation of Japan.

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Authors and Affiliations

  1. Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan

    Nobuhiro Nakazawa MD, Seded Baatar MD, Navchaa Gombodorj PhD, Yasunari Ubukata MD, Akiharu Kimura MD, PhD, Norimichi Kogure MD, PhD, Kyoichi Ogata MD, PhD, Makoto Sohda MD, PhD, Toshiki Yajima MD, PhD, Kimihiro Shimizu MD, PhD, Akira Mogi MD, PhD, Hiroyuki Kuwano MD, PhD, FACS, Hiroshi Saeki MD, PhD, FACS & Ken Shirabe MD, PhD, FACS

  2. Department of Innovative Cancer Immunotherapy, Graduate School of Medicine, Gunma University, Maebashi, Japan

    Takehiko Yokobori MD, PhD & Mariko Tsukagoshi MD, PhD

  3. Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama University Hospital, Saitama, Japan

    Kyoichi Kaira MD, PhD

  4. Tumor Microenvironment Laboratory, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Montpellier, France

    Andrei Turtoi PhD

  5. Department of Diagnostic Pathology, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan

    Tadashi Handa MS

  6. Department of Respiratory Medicine, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan

    Toshitaka Maeno MD, PhD

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  1. Nobuhiro Nakazawa MD
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  2. Takehiko Yokobori MD, PhD
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Corresponding authors

Correspondence to Nobuhiro Nakazawa MD, Takehiko Yokobori MD, PhD or Kyoichi Kaira MD, PhD.

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Disclosures

Kyoichi Kaira has received research grants and a speaker honorarium from ONO PHARMACEUTICAL CO., LTD. and Bristol-Myers Squibb K.K.

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Nakazawa, N., Yokobori, T., Kaira, K. et al. High Stromal TGFBI in Lung Cancer and Intratumoral CD8-Positive T Cells were Associated with Poor Prognosis and Therapeutic Resistance to Immune Checkpoint Inhibitors. Ann Surg Oncol 27, 933–942 (2020). https://doi.org/10.1245/s10434-019-07878-8

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