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Deficiency of IL-17A, but not the prototypical Th17 transcription factor RORγt, decreases murine spontaneous intestinal tumorigenesis

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Abstract

While inflammation has been associated with the development and progression of colorectal cancer, the exact role of the inflammatory Th17 pathway remains unclear. In this study, we aimed to determine the relative importance of IL-17A and the master regulator of the Th17 pathway, the transcription factor RORγt, in the sporadic intestinal neoplasia of APCMIN/+ mice and in human colorectal cancer. We show that levels of IL-17A are increased in human colon cancer as compared to adjacent uninvolved colon. Similarly, naïve helper T cells from colorectal cancer patients are more inducible into the Th17 pathway. Furthermore, IL-17A, IL-21, IL-22, and IL-23 are all demonstrated to be directly mitogenic to human colorectal cancer cell lines. Nevertheless, deficiency of IL-17A but not RORγt is associated with decreased spontaneous intestinal tumorigenesis in the APCMIN/+ mouse model, despite the fact that helper T cells from RORγt-deficient APCMIN/+ mice do not secrete IL-17A when subjected to Th17-polarizing conditions and that Il17a expression is decreased in the intestine of RORγt-deficient APCMIN/+ mice. Differential expression of Th17-associated cytokines between IL-17A-deficient and RORγt-deficient APCMIN/+ mice may explain the difference in adenoma development.

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Abbreviations

ANCOVA:

Analysis of covariance for independent samples

APC:

Adenomatous polyposis coli

Apc :

Adenomatous polyposis coli gene

ATCC:

American Type Culture Collection

FAP:

Familial adenomatous polyposis

HET:

Heterozygote

IACUC:

Institutional Animal Care and Use Committee

IBD:

Inflammatory bowel disease

ILC:

Innate lymphoid cell

ILC3:

Group 3 innate lymphoid cell

IRB:

Institutional review board

KO:

Knockout

MIN:

Multiple intestinal neoplasia

NKT cell:

Natural killer T cell

qRT-PCR:

Quantitative real-time polymerase chain reaction

siRNA:

Small interfering ribonucleic acid

SPF:

Specific pathogen-free

Treg:

Regulatory T cell

VABHS:

VA Boston Healthcare System

WT:

Wild type

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Acknowledgments

This work was supported by a United States Department of Veteran Affairs Office of Research and Development Career Development Award-2 (Jason S. Gold).

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Authors and Affiliations

  1. Research Service, VA Boston Healthcare System, West Roxbury, MA, USA

    Mia Shapiro, Bisweswar Nandi, Christine Pai, Dheeraj Pelluru & Rao H. Prabhala

  2. Harvard Medical School, Boston, MA, USA

    Mia Shapiro, Bisweswar Nandi, Mehmet K. Samur, Mariateresa Fulciniti, Rao H. Prabhala, Nikhil C. Munshi & Jason S. Gold

  3. Dana-Farber Cancer Center, Boston, MA, USA

    Mehmet K. Samur, Dheeraj Pelluru, Mariateresa Fulciniti, Rao H. Prabhala & Nikhil C. Munshi

  4. Medicine Service, VA Boston Healthcare System, West Roxbury, MA, USA

    Nikhil C. Munshi

  5. Surgery Service, VA Boston Healthcare System (112), 1400 VFW Parkway, West Roxbury, MA, 02132, USA

    Jason S. Gold

  6. Brigham and Women’s Hospital, Boston, MA, USA

    Jason S. Gold

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  1. Mia Shapiro
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Mia Shapiro and Bisweswar Nandi: Co-first authors.

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Shapiro, M., Nandi, B., Pai, C. et al. Deficiency of IL-17A, but not the prototypical Th17 transcription factor RORγt, decreases murine spontaneous intestinal tumorigenesis. Cancer Immunol Immunother 65, 13–24 (2016). https://doi.org/10.1007/s00262-015-1769-2

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