Synthetic retinoid-mediated preconditioning of cancer-associated fibroblasts and macrophages improves cancer response to immune checkpoint blockade

Takayuki Owaki; Tadashi Iida; Yuki Miyai; Katsuhiro Kato; Tetsunari Hase; Makoto Ishii; Ryota Ando; Kunihiko Hinohara; Tomohiro Akashi; Yasuyuki Mizutani; Takuya Ishikawa; Shinji Mii; Yukihiro Shiraki; Nobutoshi Esaki; Masami Yamamoto; Tetsuya Tsukamoto; Sachiyo Nomura; Takashi Murakami; Masahide Takahashi; Yuri Yuguchi; Motohiro Maeda; Tomoyasu Sano; Naoto Sassa; Yoshihisa Matsukawa; Hiroki Kawashima; Shusuke Akamatsu; Atsushi Enomoto

doi:10.1038/s41416-024-02734-3

Synthetic retinoid-mediated preconditioning of cancer-associated fibroblasts and macrophages improves cancer response to immune checkpoint blockade

Br J Cancer. 2024 Jul;131(2):372-386. doi: 10.1038/s41416-024-02734-3. Epub 2024 Jun 7.

Authors

Takayuki Owaki^#^{1

2}, Tadashi Iida^#^{3

4}, Yuki Miyai¹, Katsuhiro Kato⁵, Tetsunari Hase⁶, Makoto Ishii⁶, Ryota Ando¹, Kunihiko Hinohara^{7

8}, Tomohiro Akashi⁹, Yasuyuki Mizutani^{1

10}, Takuya Ishikawa¹⁰, Shinji Mii¹, Yukihiro Shiraki¹, Nobutoshi Esaki¹, Masami Yamamoto¹¹, Tetsuya Tsukamoto¹², Sachiyo Nomura^{13

14}, Takashi Murakami¹⁵, Masahide Takahashi^{16

17}, Yuri Yuguchi¹⁸, Motohiro Maeda¹⁸, Tomoyasu Sano², Naoto Sassa¹⁹, Yoshihisa Matsukawa², Hiroki Kawashima¹⁰, Shusuke Akamatsu², Atsushi Enomoto^{20

21}

Affiliations

¹ Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
² Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
³ Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan. iidatyuw@med.nagoya-u.ac.jp.
⁴ Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan. iidatyuw@med.nagoya-u.ac.jp.
⁵ Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁶ Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁷ Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁸ Institute for Advanced Research, Nagoya University, Nagoya, Japan.
⁹ Division of Systems Biology, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
¹⁰ Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
¹¹ Laboratory of Physiological Pathology, Nippon Veterinary and Life Science University, Tokyo, Japan.
¹² Division of Analytical Pathology, Oncology Innovation Center, Fujita Health University, Toyoake, Japan.
¹³ Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
¹⁴ Department of Clinical Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, Tokyo, Japan.
¹⁵ Department of Microbiology, Saitama Medical University, Saitama, Japan.
¹⁶ Department of Pathology, Fujita Health University, Toyoake, Japan.
¹⁷ International Center for Cell and Gene Therapy, Fujita Health University, Toyoake, Japan.
¹⁸ Department of Urology, Chukyo Hospital, Nagoya, Japan.
¹⁹ Department of Urology, Aichi Medical University, Nagakute, Japan.
²⁰ Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan. enomoto@iar.nagoya-u.ac.jp.
²¹ Center for One Medicine Innovative Translational Research, Gifu University Institute for Advanced Study, Gifu, Japan. enomoto@iar.nagoya-u.ac.jp.

^# Contributed equally.

Abstract

Background: The proliferation of cancer-associated fibroblasts (CAFs) hampers drug delivery and anti-tumor immunity, inducing tumor resistance to immune checkpoint blockade (ICB) therapy. However, it has remained a challenge to develop therapeutics that specifically target or modulate CAFs.

Methods: We investigated the involvement of Meflin⁺ cancer-restraining CAFs (rCAFs) in ICB efficacy in patients with clear cell renal cell carcinoma (ccRCC) and urothelial carcinoma (UC). We examined the effects of Am80 (a synthetic retinoid) administration on CAF phenotype, the tumor immune microenvironment, and ICB efficacy in cancer mouse models.

Results: High infiltration of Meflin⁺ CAFs correlated with ICB efficacy in patients with ccRCC and UC. Meflin⁺ CAF induction by Am80 administration improved ICB efficacy in the mouse models of cancer. Am80 exerted this effect when administered prior to, but not concomitant with, ICB therapy in wild-type but not Meflin-deficient mice. Am80-mediated induction of Meflin⁺ CAFs was associated with increases in antibody delivery and M1-like tumor-associated macrophage (TAM) infiltration. Finally, we showed the role of Chemerin produced from CAFs after Am80 administration in the induction of M1-like TAMs.

Conclusion: Our data suggested that Am80 administration prior to ICB therapy increases the number of Meflin⁺ rCAFs and ICB efficacy by inducing changes in TAM phenotype.

MeSH terms

Animals
Benzoates
Cancer-Associated Fibroblasts* / drug effects
Cancer-Associated Fibroblasts* / metabolism
Carcinoma, Renal Cell / drug therapy
Carcinoma, Renal Cell / immunology
Carcinoma, Renal Cell / pathology
Cell Line, Tumor
Female
Humans
Immune Checkpoint Inhibitors* / pharmacology
Immune Checkpoint Inhibitors* / therapeutic use
Kidney Neoplasms / drug therapy
Kidney Neoplasms / immunology
Kidney Neoplasms / pathology
Macrophages* / drug effects
Macrophages* / immunology
Macrophages* / metabolism
Mice
Retinoids / pharmacology
Retinoids / therapeutic use
Tetrahydronaphthalenes / pharmacology
Tumor Microenvironment* / drug effects
Tumor Microenvironment* / immunology
Tumor-Associated Macrophages / drug effects
Tumor-Associated Macrophages / immunology
Tumor-Associated Macrophages / metabolism

Substances

Immune Checkpoint Inhibitors
Tetrahydronaphthalenes
Retinoids
tamibarotene
Benzoates

Abstract

MeSH terms

Substances

Grants and funding