【Publications】Stromal reprogramming through dual PDGFRα/β blockade boosts the efficacy of anti-PD-1 immunotherapy in fibrotic tumors

January 9 2023

Takatsugu Ishimoto

Paper information

Title：
Stromal reprogramming through dual PDGFRα/β blockade boosts the efficacy of anti-PD-1 immunotherapy in fibrotic tumors

Akiyama T**, Yasuda T**, Uchihara T**, Yasuda-Yoshihara N, Tan BJY, Yonemura A, Semba T, Yamasaki J, Komohara Y, Ohnishi K, Wei F, Fu L, Zhang J, Kitamura F, Yamashita K, Eto K, Iwagami S, Tsukamoto H, Umemoto T, Masuda M, Nagano O, Satou Y, Saya H, Tan P, Baba H, Ishimoto T*.

(*corresponding authors, **equally contributed)

Cancer Res. 2022 Dec 21: CAN-22-1890. doi: 10.1158/0008-5472.CAN-22-1890.

Significance

Current study provides a rationale for immune reactivation through stromal amelioration by PDGFR α/β dual blockade, which restores the immunosuppressive microenvironment and enhances the efficacy of immune checkpoint inhibitors in fibrotic cancer patients

Abstract

Excess stroma and cancer-associated fibroblasts (CAFs) enhance cancer progression and faciliate 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 (GC), and PDGF receptor beta (PDGFRβ) was predominantly expressed in diffuse-type GC 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 GC 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.

Representative Figure

Graphical Abstract

熊本大学プレスリリース (Japanese)

熊本大学プレスリリース (Japanese) release221222-1.pdf