Stromal Reprogramming through Dual PDGFRα/β Blockade Boosts the Efficacy of Anti–PD-1 Immunotherapy in Fibrotic Tumors-Reference-Cited by-同舟云学术

Stromal Reprogramming through Dual PDGFRα/β Blockade Boosts the Efficacy of Anti–PD-1 Immunotherapy in Fibrotic Tumors

Published:2022-12-21 Issue:5 Volume:83 Page:753-770
ISSN:0008-5472
Container-title:Cancer Research
language:en
Short-container-title:

Author:

Akiyama Takahiko¹²^ORCID,Yasuda Tadahito¹²^ORCID,Uchihara Tomoyuki¹²^ORCID,Yasuda-Yoshihara Noriko¹²^ORCID,Tan Benjy J.Y.³^ORCID,Yonemura Atsuko¹²^ORCID,Semba Takashi¹²^ORCID,Yamasaki Juntaro⁴^ORCID,Komohara Yoshihiro⁵^ORCID,Ohnishi Koji⁶^ORCID,Wei Feng¹²^ORCID,Fu Lingfeng¹²^ORCID,Zhang Jun¹²^ORCID,Kitamura Fumimasa¹²^ORCID,Yamashita Kohei¹^ORCID,Eto Kojiro¹^ORCID,Iwagami Shiro¹^ORCID,Tsukamoto Hirotake⁷^ORCID,Umemoto Terumasa⁸^ORCID,Masuda Mari⁹^ORCID,Nagano Osamu⁴^ORCID,Satou Yorifumi³^ORCID,Saya Hideyuki⁴¹⁰^ORCID,Tan Patrick¹¹^ORCID,Baba Hideo¹¹²^ORCID,Ishimoto Takatsugu¹²^ORCID

Affiliation:

1. 1Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

2. 2Gastrointestinal Cancer Biology, International Research Center of Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.

3. 3Division of Genomics and Transcriptomics, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan.

4. 4Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan.

5. 5Department of Cell Pathology, Kumamoto University, Kumamoto, Japan.

6. 6Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Japan.

7. 7Division of Clinical Immunology and Cancer Immunotherapy, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

8. 8Laboratory of Hematopoietic Stem Cell Engineering, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.

9. 9Department of Proteomics, National Cancer Center Research Institute, Tokyo, Japan.

10. 10Division of Gene Regulation, Cancer Center, Fujita Health University, Toyoake, Japan.

11. 11Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore.

12. 12Center for Metabolic Regulation of Healthy Aging, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

Abstract

AbstractExcess stroma and cancer-associated fibroblasts (CAF) enhance cancer progression and facilitate immune evasion. Insights into the mechanisms by which the stroma manipulates the immune microenvironment could help improve cancer treatment. Here, we aimed to elucidate potential approaches for stromal reprogramming and improved cancer immunotherapy. Platelet-derived growth factor C (PDGFC) and D expression were significantly associated with a poor prognosis in patients with gastric cancer, and PDGF receptor beta (PDGFRβ) was predominantly expressed in diffuse-type gastric cancer stroma. CAFs stimulated with PDGFs exhibited markedly increased expression of CXCL1, CXCL3, CXCL5, and CXCL8, which are involved in polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) recruitment. Fibrotic gastric cancer xenograft tumors exhibited increased PMN-MDSC accumulation and decreased lymphocyte infiltration, as well as resistance to anti–PD-1. Single-cell RNA sequencing and spatial transcriptomics revealed that PDGFRα/β blockade reversed the immunosuppressive microenvironment through stromal modification. Finally, combining PDGFRα/β blockade and anti–PD-1 treatment synergistically suppressed the growth of fibrotic tumors. These findings highlight the impact of stromal reprogramming on immune reactivation and the potential for combined immunotherapy for patients with fibrotic cancer.Significance:Stromal targeting with PDGFRα/β dual blockade reverses the immunosuppressive microenvironment and enhances the efficacy of immune checkpoint inhibitors in fibrotic cancer.See related commentary by Tauriello, p. 655

Funder

Japan Society for the Promotion of Science

Naito Foundation

Shinnihon Foundation of Advanced Medical Treatment Research

Eli Lilly and Company

Fusion Oriented REsearch for disruptive Science and Technology

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

Link

https://aacrjournals.org/cancerres/article-pdf/doi/10.1158/0008-5472.CAN-22-1890/3231563/can-22-1890.pdf