Targeting heterogeneous tumor microenvironments in pancreatic cancer mouse models of metastasis by TGF-β depletion
Sophia Y. Chen, … , William L. Hwang, Lei Zheng
Sophia Y. Chen, … , William L. Hwang, Lei Zheng
Published September 19, 2024
Citation Information: JCI Insight. 2024;9(21):e182766. https://doi.org/10.1172/jci.insight.182766.
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Research Article Immunology Oncology

Targeting heterogeneous tumor microenvironments in pancreatic cancer mouse models of metastasis by TGF-β depletion

Abstract

The dual tumor-suppressive and -promoting functions of TGF-β signaling has made its targeting challenging. We examined the effects of TGF-β depletion by AVID200/BMS-986416 (TGF-β-TRAP), a TGF-β ligand trap, on the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) murine models with different organ-specific metastasis. Our study demonstrated that TGF-β-TRAP potentiates the efficacy of anti–programmed cell death 1 (anti–PD-1) in a PDAC orthotopic murine model with liver metastasis tropism, significantly reducing liver metastases. We further demonstrated the heterogeneous response of cytotoxic effector T cells to combination TGF-β-TRAP and anti–PD-1 treatment across several tumor models. Single-nuclear RNA sequencing suggested that TGF-β-TRAP modulates cancer-associated fibroblast (CAF) heterogeneity and suppresses neutrophil degranulation and CD4+ T cell response to neutrophil degranulation. Ligand-receptor analysis indicated that TGF-β-TRAP may modulate the CCL5/CCR5 axis as well as costimulatory and checkpoint signaling from CAFs and myeloid cells. Notably, the most highly expressed ligands of CCR5 shifted from the immunosuppressive CCL5 to CCL7 and CCL8, which may mediate the immune agonist activity of CCR5 following TGF-β-TRAP and anti–PD-1 combination treatment. This study suggested that TGF-β depletion modulates CAF heterogeneity and potentially reprograms CAFs and myeloid cells into antitumor immune agonists in PDAC, supporting the validation of such effects in human specimens.

Authors

Sophia Y. Chen, Heng-Chung Kung, Birginia Espinoza, India Washington, Kai Chen, Jianxin Wang, Haley Zlomke, Michael Loycano, Rulin Wang, Michael Pickup, William R. Burns III, Juan Fu, William L. Hwang, Lei Zheng

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Figure 1

The combination of TGF-β-TRAP and a-PD-1 slows the rate of tumor growth and prolongs survival in PDAC mouse models with KPC-4545 cell line.

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The combination of TGF-β-TRAP and a-PD-1 slows the rate of tumor growth ...
(A) Treatment schema for PDAC orthotopic model tumor growth experiment using AVID200, the human surrogate form of TGF-β-TRAP. Pretreatment US was performed on day 6. Mice were treated with AVID200 (5 mg/kg i.p. twice/week), a-PD-1 (5 mg/kg i.p. twice/week), or IgG control (5 mg/kg i.p. twice/week) for 3 weeks. (B) PDAC orthotopic tumor size was evaluated by US weekly until day 29 in mice treated with different combinations of AVID200 and a-PD-1 (n = 5 mice per group). Data represent mean ±SEM. (C and D) Representative H&E images of liver (C) and lung metastatic (D) sites in PDAC orthotopic mouse model syngeneic wild-type C57BL/6 mice. Original magnification ×5. (E and F) When PDAC orthotopic tumor mice reached survival endpoint, necropsies were performed, and the number of mice with liver metastases for the KPC-4545 model (E) and lung metastases for the KPC-3403 model (F) were identified grossly and histologically (n = 8–10 mice per group). (G) Treatment schema for PDAC hemispleen model using mTGF-β-TRAP, the mouse surrogate form of TGF-β-TRAP. Mice were treated with mTGF-β-TRAP (15 mg/kg i.p. once/week), a-PD-1 (5 mg/kg i.p. twice/week), or IgG control (5 mg/kg i.p. twice/week) for 3 weeks. (H) Kaplan-Meier survival curves of PDAC hemispleen model mice treated with different combinations of mTGF-β-TRAP and a-PD-1 (n = 10 mice per group). US, ultrasound. Unpaired t test was used to compare day 29 tumor volumes. Log-rank test was used for survival analysis. A χ2 test was used to examine the correlation between treatment groups and metastasis rates. *, P < 0.05; **, P < 0.01; ***, P < 0.001.