Nobuhiro Nakazawa1, Takehiko Yokobori2, Kyoichi Kaira3, Andrei Turtoi4, Seded Baatar5, Navchaa Gombodorj5, Tadashi Handa6, Mariko Tsukagoshi7, Yasunari Ubukata5, Akiharu Kimura5, Norimichi Kogure5, Kyoichi Ogata5, Toshitaka Maeno8, Makoto Sohda5, Toshiki Yajima5, Kimihiro Shimizu5, Akira Mogi5, Hiroyuki Kuwano5, Hiroshi Saeki5, Ken Shirabe5. 1. Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan. nakazawa75@yahoo.co.jp. 2. Department of Innovative Cancer Immunotherapy, Graduate School of Medicine, Gunma University, Maebashi, Japan. bori45@gunma-u.ac.jp. 3. Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama University Hospital, Saitama, Japan. kkaira1970@yahoo.co.jp. 4. Tumor Microenvironment Laboratory, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Montpellier, France. 5. Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan. 6. Department of Diagnostic Pathology, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan. 7. Department of Innovative Cancer Immunotherapy, Graduate School of Medicine, Gunma University, Maebashi, Japan. 8. Department of Respiratory Medicine, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan.
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.
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 cancerpatients 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:CancerTGFBI 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.
Authors: Sandra Cascio; Chelsea Chandler; Linan Zhang; Sarah Sinno; Bingsi Gao; Sayali Onkar; Tullia C Bruno; Dario A A Vignali; Haider Mahdi; Hatice U Osmanbeyoglu; Anda M Vlad; Lan G Coffman; Ronald J Buckanovich Journal: Sci Adv Date: 2021-11-12 Impact factor: 14.957