Mucciolo et al. characterized the role of IL17A in modulating tumor fibroblasts and in creating an immune-suppressive microenvironment in a pancreatic ductal adenocarcinoma mouse model. Loss of IL17A increased the amount of, decreased the stiffness of, and altered the arrangement of collagen fibers; increased activated CD80+ macrophages and effector CD4+ and CD8+ T cell infiltration; and decreased immunosuppressive Foxp3+ T cells. Absence or inhibition of IL17A increased transcripts associated with Th1 recruitment, T cell activation, and effector phenotype; decreased transcripts associated with granulocyte/monocyte movement; and decreased tumor cell invasion.
Contributed by Shishir Pant
ABSTRACT: A hallmark of cancer, including pancreatic ductal adenocarcinoma (PDA), is a massive stromal and inflammatory reaction. Many efforts have been made to identify the anti- or protumoral role of cytokines and immune subpopulations within the stroma. Here, we investigated the role of interleukin-17A (IL17A) and its effect on tumor fibroblasts and the tumor microenvironment. We used a spontaneous PDA mouse model (KPC) crossed to IL17A knockout mice to show an extensive desmoplastic reaction, without impaired immune infiltration. Macrophages, especially CD80(+) and T cells, were more abundant at the earlier time point. In T cells, a decrease in FoxP3(+) cells and an increase in CD8(+) T cells were observed in KPC/IL17A(-/-) mice. Fibroblasts isolated from IL17A(+/+) and IL17A(-/-) KPC mice revealed very different messenger RNA (mRNA) and protein profiles. IL17A(-/-) fibroblasts displayed the ability to restrain tumor cell invasion by producing factors involved in extracellular matrix remodeling, increasing T cell recruitment, and producing higher levels of cytokines and chemokines favoring T helper 1 cell recruitment and activation and lower levels of those recruiting myeloid/granulocytic immune cells. Single-cell quantitative PCR on isolated fibroblasts confirmed a very divergent profile of IL17A-proficient and -deficient cells. All these features can be ascribed to increased levels of IL17F observed in the sera of IL17A(-/-) mice, and to the higher expression of its cognate receptor (IL17RC) specifically in IL17A(-/-) cancer-associated fibroblasts (CAFs). In addition to the known effects on neoplastic cell transformation, the IL17 cytokine family uniquely affects fibroblasts, representing a suitable candidate target for combinatorial immune-based therapies in PDA.
Author Info: (1) Laboratory of Tumor Immunology, Center for Experimental Research and Medical Studies, Citt della Salute e della Scienza di Torino, University of Torino, 10126 Torino, Italy. De
Author Info: (1) Laboratory of Tumor Immunology, Center for Experimental Research and Medical Studies, Citt della Salute e della Scienza di Torino, University of Torino, 10126 Torino, Italy. Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy. (2) Laboratory of Tumor Immunology, Center for Experimental Research and Medical Studies, Citt della Salute e della Scienza di Torino, University of Torino, 10126 Torino, Italy. Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy. (3) Laboratory of Tumor Immunology, Center for Experimental Research and Medical Studies, Citt della Salute e della Scienza di Torino, University of Torino, 10126 Torino, Italy. Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy. (4) Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. (5) Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (6) Laboratory of Tumor Immunology, Center for Experimental Research and Medical Studies, Citt della Salute e della Scienza di Torino, University of Torino, 10126 Torino, Italy. Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy. (7) Laboratory of Tumor Immunology, Center for Experimental Research and Medical Studies, Citt della Salute e della Scienza di Torino, University of Torino, 10126 Torino, Italy. Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy. Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115. (8) Laboratory of Tumor Immunology, Center for Experimental Research and Medical Studies, Citt della Salute e della Scienza di Torino, University of Torino, 10126 Torino, Italy. (9) Medical Oncology Division, Centro Oncologico Ematologico Subalpino, Citt della Salute e della Scienza di Torino, Department of Oncology, University of Torino, 10126 Torino, Italy. (10) Applied Research Center (ARC-NET), University of Verona, 37134 Verona, Italy. Department of Diagnostics and Public Health, University of Verona, 37134 Verona, Italy. (11) Applied Research Center (ARC-NET), University of Verona, 37134 Verona, Italy. Department of Diagnostics and Public Health, University of Verona, 37134 Verona, Italy. (12) Laboratory of Immunotherapy, Institute of Microbiology v.v.i., Czech Academy of Sciences, Prague 14220, Czech Republic. Faculty of Science, Charles University, Prague 12800, Czech Republic. (13) Laboratory of Immunotherapy, Institute of Microbiology v.v.i., Czech Academy of Sciences, Prague 14220, Czech Republic. Faculty of Medicine, Charles University, Prague 12108, Czech Republic. (14) Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy. (15) Laboratory of Immunotherapy, Institute of Microbiology v.v.i., Czech Academy of Sciences, Prague 14220, Czech Republic. (16) Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; tak.mak@uhnresearch.ca franco.novelli@unito.it paola.cappello@unito.it. Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada. Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. Department of Medicine, University of Hong Kong, 999077 Hong Kong. (17) Laboratory of Tumor Immunology, Center for Experimental Research and Medical Studies, Citt della Salute e della Scienza di Torino, University of Torino, 10126 Torino, Italy; tak.mak@uhnresearch.ca franco.novelli@unito.it paola.cappello@unito.it. Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy. Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy. (18) Laboratory of Tumor Immunology, Center for Experimental Research and Medical Studies, Citt della Salute e della Scienza di Torino, University of Torino, 10126 Torino, Italy; tak.mak@uhnresearch.ca franco.novelli@unito.it paola.cappello@unito.it. Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy. Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy.
