Bronchoalveolar lavage fluid reveals factors contributing to the efficacy of PD-1 blockade in lung cancer
Kentaro Masuhiro, … , Tomonori Hirashima, Atsushi Kumanogoh
Kentaro Masuhiro, … , Tomonori Hirashima, Atsushi Kumanogoh
Published April 7, 2022
Citation Information: JCI Insight. 2022;7(9):e157915. https://doi.org/10.1172/jci.insight.157915.
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Research Article Immunology Oncology

Bronchoalveolar lavage fluid reveals factors contributing to the efficacy of PD-1 blockade in lung cancer

Abstract

Bronchoalveolar lavage is commonly performed to assess inflammation and identify responsible pathogens in lung diseases. Findings from bronchoalveolar lavage might be used to evaluate the immune profile of the lung tumor microenvironment (TME). To investigate whether bronchoalveolar lavage fluid (BALF) analysis can help identify patients with non–small cell lung cancer (NSCLC) who respond to immune checkpoint inhibitors (ICIs), BALF and blood were prospectively collected before initiating nivolumab. The secreted molecules, microbiome, and cellular profiles based on BALF and blood analysis of 12 patients were compared with regard to therapeutic effect. Compared with ICI nonresponders, responders showed significantly higher CXCL9 levels and a greater diversity of the lung microbiome profile in BALF, along with a greater frequency of the CD56+ subset in blood T cells, whereas no significant difference in PD-L1 expression was found in tumor cells. Antibiotic treatment in a preclinical lung cancer model significantly decreased CXCL9 in the lung TME, resulting in reduced sensitivity to anti–PD-1 antibody, which was reversed by CXCL9 induction in tumor cells. Thus, CXCL9 might be associated with the lung TME microbiome, and the balance of CXCL9 and lung TME microbiome could contribute to nivolumab sensitivity in patients with NSCLC. BALF analysis can help predict the efficacy of ICIs when performed along with currently approved examinations.

Authors

Kentaro Masuhiro, Motohiro Tamiya, Kosuke Fujimoto, Shohei Koyama, Yujiro Naito, Akio Osa, Takashi Hirai, Hidekazu Suzuki, Norio Okamoto, Takayuki Shiroyama, Kazumi Nishino, Yuichi Adachi, Takuro Nii, Yumi Kinugasa-Katayama, Akiko Kajihara, Takayoshi Morita, Seiya Imoto, Satoshi Uematsu, Takuma Irie, Daisuke Okuzaki, Taiki Aoshi, Yoshito Takeda, Toru Kumagai, Tomonori Hirashima, Atsushi Kumanogoh

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Figure 4

Overexpression of CXCL9 in KPOVA enhanced recruitment of tumor-specific CXCR3+CD8+ T cells and reduced tumor growth.

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Overexpression of CXCL9 in KPOVA enhanced recruitment of tumor-specific ...
(A) Schematic of treatment schedule. Mice were inoculated with 1 × 106 KPOVA cells transfected with empty vector (mock) or with KPOVA-Cxcl9 cells. Then, they were treated with either anti–PD-1 antibodies or isotype control for 2 weeks starting 3 days after tumor inoculation. BALF and tumors were collected after sacrifice on day 14. (B) Tumor weight of mice inoculated with KPOVA-mock or KPOVA-Cxcl9 cells and treated with isotype (black) or anti–PD-1 (red). Tumor weight encompasses the total weight of the tumor enucleated from the lung tissue and tumors invading the mediastinum and chest wall. Data are presented as the mean ± SEM. *P < 0.05, *** P < 0.001; statistical significance determined by 1-way ANOVA with Tukey’s multiple comparison test (n = 9–16 mice/group). (C and D) Total counts of (C) CD8+ and CXCR3+CD8+ T cells and (D) tetramer+ and tetramer+CXCR3+CD8+ T cells in BALF were analyzed by flow cytometry. BALF was collected from mice inoculated with KPOVA-mock or KPOVA-Cxcl9 cells and treated with isotype (black) or anti–PD-1 (red). Data are presented as the mean ± SEM. *P < 0.05, ** P < 0.01, ***P < 0.001; statistical significance determined by 1-way ANOVA with Tukey’s multiple comparison test (n = 4–6 mice/group). (E) Representative contour plots and summary of the frequency of OVA-tetramer+PD-1+ subsets in CXCR3+CD8+ T cells compared between mice inoculated with KPOVA-mock or KPOVA-Cxcl9 cells and treated with isotype control. Data are presented as the mean ± SEM. Statistical significance determined by Student’s t test (n = 5–6 mice/group). (F) Summary of the total counts of OVA-tetramer+PD-1+CD8+ T cells in BALF compared between mice inoculated with KPOVA-mock or KPOVA-Cxcl9 and treated with isotype control. Data are presented as the mean ± SEM. *P < 0.05; statistical significance determined by Student’s t test (n = 5–6 mice/group). (B–F) Data are representative of at least 2 independent experiments.