TY - JOUR
T1 - Macrophage activity at the site of tumor ablation can promote murine urothelial cancer via transforming growth factor-β1
AU - Kimura, Yasushi
AU - Fujimori, Masashi
AU - Rajagopalan, Neeraj Raghuraman
AU - Poudel, Krish
AU - Kim, Kwanghee
AU - Nagar, Karan
AU - Vroomen, Laurien G. PH.
AU - Reis, Henning
AU - Al-Ahmadie, Hikmat
AU - Coleman, Jonathan A.
AU - Srimathveeravalli, Govindarajan
N1 - Funding Information: GS acknowledges grant and funding support from the Thompson Foundation, the National Cancer Institute and the National Institute of Diabetes, and Digestive and Kidney Diseases of the National Institutes of Health under Award Number R01CA236615 and R01DK129990, the Dept. of Defense CDMRP PRCRP Award CA170630 and CA190888, and the Institute for Applied Life Sciences in the University of Massachusetts at Amherst. Publisher Copyright: Copyright © 2023 Kimura, Fujimori, Rajagopalan, Poudel, Kim, Nagar, Vroomen, Reis, Al-Ahmadie, Coleman and Srimathveeravalli.
PY - 2023/1/24
Y1 - 2023/1/24
N2 - Cell death and injury at the site of tumor ablation attracts macrophages. We sought to understand the status and activity of these cells while focusing on transforming growth factor-β1 (TGF-β1), a potent immunosuppressive and tumorigenic cytokine. Patients with urothelial cancer who underwent ablation using electrocautery or laser demonstrated increased infiltration and numbers of CD8+ T cells, along with FoxP3+ regulatory T cells, CD68+ macrophages and elevated levels of TGF-β1 in recurrent tumors. Similar findings were reproduced in a mouse model of urothelial cancer (MB49) by partial tumor ablation with irreversible electroporation (IRE). Stimulation of bone marrow derived macrophages with MB49 cell debris produced using IRE elicited strong M2 polarization, with exuberant secretion of TGF-β1. The motility, phenotypic markers and cytokine secretion by macrophages could be muted by treatment with Pirfenidone (PFD), a clinically approved drug targeting TGF-β1 signaling. MB49 cancer cells exposed to TGF-β1 exhibited increased migration, invasiveness and upregulation of epithelial-mesenchymal transition markers α-Smooth Muscle Actin and Vimentin. Such changes in MB49 cells were reduced by treatment with PFD even during stimulation with TGF-β1. IRE alone yielded better local tumor control when compared with control or PFD alone, while also reducing the overall number of lung metastases. Adjuvant PFD treatment did not provide additional benefit under in vivo conditions.
AB - Cell death and injury at the site of tumor ablation attracts macrophages. We sought to understand the status and activity of these cells while focusing on transforming growth factor-β1 (TGF-β1), a potent immunosuppressive and tumorigenic cytokine. Patients with urothelial cancer who underwent ablation using electrocautery or laser demonstrated increased infiltration and numbers of CD8+ T cells, along with FoxP3+ regulatory T cells, CD68+ macrophages and elevated levels of TGF-β1 in recurrent tumors. Similar findings were reproduced in a mouse model of urothelial cancer (MB49) by partial tumor ablation with irreversible electroporation (IRE). Stimulation of bone marrow derived macrophages with MB49 cell debris produced using IRE elicited strong M2 polarization, with exuberant secretion of TGF-β1. The motility, phenotypic markers and cytokine secretion by macrophages could be muted by treatment with Pirfenidone (PFD), a clinically approved drug targeting TGF-β1 signaling. MB49 cancer cells exposed to TGF-β1 exhibited increased migration, invasiveness and upregulation of epithelial-mesenchymal transition markers α-Smooth Muscle Actin and Vimentin. Such changes in MB49 cells were reduced by treatment with PFD even during stimulation with TGF-β1. IRE alone yielded better local tumor control when compared with control or PFD alone, while also reducing the overall number of lung metastases. Adjuvant PFD treatment did not provide additional benefit under in vivo conditions.
KW - ablation
KW - bladder cancer
KW - irreversible electroporation
KW - macrophages
KW - transforming growing factor-β1
UR - http://www.scopus.com/inward/record.url?scp=85147444326&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fimmu.2023.1070196
DO - https://doi.org/10.3389/fimmu.2023.1070196
M3 - Article
C2 - 36761730
SN - 1664-3224
VL - 14
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 1070196
ER -