TY - JOUR
T1 - Stromal Reprogramming through Dual PDGFRa/b Blockade Boosts the Efficacy of Anti–PD-1 Immunotherapy in Fibrotic Tumors
AU - Akiyama, Takahiko
AU - Yasuda, Tadahito
AU - Uchihara, Tomoyuki
AU - Yasuda-Yoshihara, Noriko
AU - Tan, Benjy J.Y.
AU - Yonemura, Atsuko
AU - Semba, Takashi
AU - Yamasaki, Juntaro
AU - Komohara, Yoshihiro
AU - Ohnishi, Koji
AU - Wei, Feng
AU - Fu, Lingfeng
AU - Zhang, Jun
AU - Kitamura, Fumimasa
AU - Yamashita, Kohei
AU - Eto, Kojiro
AU - Iwagami, Shiro
AU - Tsukamoto, Hirotake
AU - Umemoto, Terumasa
AU - Masuda, Mari
AU - Nagano, Osamu
AU - Satou, Yorifumi
AU - Saya, Hideyuki
AU - Tan, Patrick
AU - Baba, Hideo
AU - Ishimoto, Takatsugu
N1 - Publisher Copyright:
©2022 American Association for Cancer Research.
PY - 2023/3/1
Y1 - 2023/3/1
N2 - Excess 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 (PDGFRb) 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 PDGFRa/b blockade reversed the immunosuppressive microenvironment through stromal modification. Finally, combining PDGFRa/b 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 PDGFRa/b dual blockade reverses the immunosuppressive microenvironment and enhances the efficacy of immune checkpoint inhibitors in fibrotic cancer.
AB - Excess 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 (PDGFRb) 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 PDGFRa/b blockade reversed the immunosuppressive microenvironment through stromal modification. Finally, combining PDGFRa/b 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 PDGFRa/b dual blockade reverses the immunosuppressive microenvironment and enhances the efficacy of immune checkpoint inhibitors in fibrotic cancer.
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UR - http://www.scopus.com/inward/citedby.url?scp=85149172823&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-22-1890
DO - 10.1158/0008-5472.CAN-22-1890
M3 - Article
C2 - 36543251
AN - SCOPUS:85149172823
SN - 0008-5472
VL - 83
SP - 753
EP - 770
JO - Cancer Research
JF - Cancer Research
IS - 5
ER -
