Gut epithelial Interleukin-17 receptor A signaling can modulate distant tumors growth through microbial regulation

Vidhi Chandra; Le Li; Olivereen Le Roux; Yu Zhang; Rian M. Howell; Dhwani N. Rupani; Seyda Baydogan; Haiyan D. Miller; Erick Marcelo Riquelme Sanchez; Joseph Petrosino; Michael P. Kim; Krishna P.L. Bhat; James R. White; Jay K. Kolls; Yuliya Pylayeva-Gupta; Florencia McAllister

doi:10.1016/j.ccell.2023.12.006

Gut epithelial Interleukin-17 receptor A signaling can modulate distant tumors growth through microbial regulation

Vidhi Chandra, Le Li, Olivereen Le Roux, Yu Zhang, Rian M. Howell, Dhwani N. Rupani, Seyda Baydogan, Haiyan D. Miller, Erick Marcelo Riquelme Sanchez, Joseph Petrosino, Michael P. Kim, Krishna P.L. Bhat, James R. White, Jay K. Kolls, Yuliya Pylayeva-Gupta, Florencia McAllister

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

Microbes influence cancer initiation, progression and therapy responsiveness. IL-17 signaling contributes to gut barrier immunity by regulating microbes but also drives tumor growth. A knowledge gap remains regarding the influence of enteric IL-17-IL-17RA signaling and their microbial regulation on the behavior of distant tumors. We demonstrate that gut dysbiosis induced by systemic or gut epithelial deletion of IL-17RA induces growth of pancreatic and brain tumors due to excessive development of Th17, primary source of IL-17 in human and mouse pancreatic ductal adenocarcinoma, as well as B cells that circulate to distant tumors. Microbial dependent IL-17 signaling increases DUOX2 signaling in tumor cells. Inefficacy of pharmacological inhibition of IL-17RA is overcome with targeted microbial ablation that blocks the compensatory loop. These findings demonstrate the complexities of IL-17-IL-17RA signaling in different compartments and the relevance for accounting for its homeostatic host defense function during cancer therapy.

Original language	English (US)
Pages (from-to)	85-100.e6
Journal	Cancer cell
Volume	42
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2023.12.006
State	Published - Jan 8 2024

Keywords

B cells
IL-17
intestinal homeostasis
microbiome
pancreatic cancer

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccell.2023.12.006

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Chandra, V., Li, L., Le Roux, O., Zhang, Y., Howell, R. M., Rupani, D. N., Baydogan, S., Miller, H. D., Riquelme Sanchez, E. M., Petrosino, J., Kim, M. P., Bhat, K. P. L., White, J. R., Kolls, J. K., Pylayeva-Gupta, Y., & McAllister, F. (2024). Gut epithelial Interleukin-17 receptor A signaling can modulate distant tumors growth through microbial regulation. Cancer cell, 42(1), 85-100.e6. https://doi.org/10.1016/j.ccell.2023.12.006

Chandra, V, Li, L, Le Roux, O, Zhang, Y, Howell, RM, Rupani, DN, Baydogan, S, Miller, HD, Riquelme Sanchez, EM, Petrosino, J, Kim, MP, Bhat, KPL, White, JR, Kolls, JK, Pylayeva-Gupta, Y & McAllister, F 2024, 'Gut epithelial Interleukin-17 receptor A signaling can modulate distant tumors growth through microbial regulation', Cancer cell, vol. 42, no. 1, pp. 85-100.e6. https://doi.org/10.1016/j.ccell.2023.12.006

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abstract = "Microbes influence cancer initiation, progression and therapy responsiveness. IL-17 signaling contributes to gut barrier immunity by regulating microbes but also drives tumor growth. A knowledge gap remains regarding the influence of enteric IL-17-IL-17RA signaling and their microbial regulation on the behavior of distant tumors. We demonstrate that gut dysbiosis induced by systemic or gut epithelial deletion of IL-17RA induces growth of pancreatic and brain tumors due to excessive development of Th17, primary source of IL-17 in human and mouse pancreatic ductal adenocarcinoma, as well as B cells that circulate to distant tumors. Microbial dependent IL-17 signaling increases DUOX2 signaling in tumor cells. Inefficacy of pharmacological inhibition of IL-17RA is overcome with targeted microbial ablation that blocks the compensatory loop. These findings demonstrate the complexities of IL-17-IL-17RA signaling in different compartments and the relevance for accounting for its homeostatic host defense function during cancer therapy.",

keywords = "B cells, IL-17, intestinal homeostasis, microbiome, pancreatic cancer",

author = "Vidhi Chandra and Le Li and {Le Roux}, Olivereen and Yu Zhang and Howell, {Rian M.} and Rupani, {Dhwani N.} and Seyda Baydogan and Miller, {Haiyan D.} and {Riquelme Sanchez}, {Erick Marcelo} and Joseph Petrosino and Kim, {Michael P.} and Bhat, {Krishna P.L.} and White, {James R.} and Kolls, {Jay K.} and Yuliya Pylayeva-Gupta and Florencia McAllister",

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AU - Chandra, Vidhi

AU - Li, Le

AU - Le Roux, Olivereen

AU - Zhang, Yu

AU - Howell, Rian M.

AU - Rupani, Dhwani N.

AU - Baydogan, Seyda

AU - Miller, Haiyan D.

AU - Riquelme Sanchez, Erick Marcelo

AU - Petrosino, Joseph

AU - Kim, Michael P.

AU - Bhat, Krishna P.L.

AU - White, James R.

AU - Kolls, Jay K.

AU - Pylayeva-Gupta, Yuliya

AU - McAllister, Florencia

PY - 2024/1/8

Y1 - 2024/1/8

N2 - Microbes influence cancer initiation, progression and therapy responsiveness. IL-17 signaling contributes to gut barrier immunity by regulating microbes but also drives tumor growth. A knowledge gap remains regarding the influence of enteric IL-17-IL-17RA signaling and their microbial regulation on the behavior of distant tumors. We demonstrate that gut dysbiosis induced by systemic or gut epithelial deletion of IL-17RA induces growth of pancreatic and brain tumors due to excessive development of Th17, primary source of IL-17 in human and mouse pancreatic ductal adenocarcinoma, as well as B cells that circulate to distant tumors. Microbial dependent IL-17 signaling increases DUOX2 signaling in tumor cells. Inefficacy of pharmacological inhibition of IL-17RA is overcome with targeted microbial ablation that blocks the compensatory loop. These findings demonstrate the complexities of IL-17-IL-17RA signaling in different compartments and the relevance for accounting for its homeostatic host defense function during cancer therapy.

AB - Microbes influence cancer initiation, progression and therapy responsiveness. IL-17 signaling contributes to gut barrier immunity by regulating microbes but also drives tumor growth. A knowledge gap remains regarding the influence of enteric IL-17-IL-17RA signaling and their microbial regulation on the behavior of distant tumors. We demonstrate that gut dysbiosis induced by systemic or gut epithelial deletion of IL-17RA induces growth of pancreatic and brain tumors due to excessive development of Th17, primary source of IL-17 in human and mouse pancreatic ductal adenocarcinoma, as well as B cells that circulate to distant tumors. Microbial dependent IL-17 signaling increases DUOX2 signaling in tumor cells. Inefficacy of pharmacological inhibition of IL-17RA is overcome with targeted microbial ablation that blocks the compensatory loop. These findings demonstrate the complexities of IL-17-IL-17RA signaling in different compartments and the relevance for accounting for its homeostatic host defense function during cancer therapy.

KW - B cells

KW - IL-17

KW - intestinal homeostasis

KW - microbiome

KW - pancreatic cancer

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Gut epithelial Interleukin-17 receptor A signaling can modulate distant tumors growth through microbial regulation

Abstract

Keywords

ASJC Scopus subject areas

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