Title | Simultaneous Loss of Both Atypical Protein Kinase C Genes in the Intestinal Epithelium Drives Serrated Intestinal Cancer by Impairing Immunosurveillance. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Nakanishi Y, Duran A, L'Hermitte A, Shelton PM, Nakanishi N, Reina-Campos M, Huang J, Soldevila F, Baaten BJG, Tauriello DVF, Castilla EA, Bhangoo MS, Bao F, Sigal D, Diaz-Meco MT, Moscat J |
Journal | Immunity |
Volume | 49 |
Issue | 6 |
Pagination | 1132-1147.e7 |
Date Published | 2018 12 18 |
ISSN | 1097-4180 |
Keywords | Adult, Aged, Aged, 80 and over, Animals, B7-H1 Antigen, CD8-Positive T-Lymphocytes, Cell Transformation, Neoplastic, Colorectal Neoplasms, Female, Humans, Immunologic Surveillance, Intestinal Mucosa, Intestinal Neoplasms, Isoenzymes, Male, Mice, Knockout, Mice, Transgenic, Middle Aged, Protein Kinase C, Receptors, Transforming Growth Factor beta |
Abstract | Serrated adenocarcinoma, an alternative pathway for colorectal cancer (CRC) development, accounts for 15%-30% of all CRCs and is aggressive and treatment resistant. We show that the expression of atypical protein kinase C ζ (PKCζ) and PKCλ/ι was reduced in human serrated tumors. Simultaneous inactivation of the encoding genes in the mouse intestinal epithelium resulted in spontaneous serrated tumorigenesis that progressed to advanced cancer with a strongly reactive and immunosuppressive stroma. Whereas epithelial PKCλ/ι deficiency led to immunogenic cell death and the infiltration of CD8 T cells, which repressed tumor initiation, PKCζ loss impaired interferon and CD8 T cell responses, which resulted in tumorigenesis. Combined treatment with a TGF-β receptor inhibitor plus anti-PD-L1 checkpoint blockade showed synergistic curative activity. Analysis of human samples supported the relevance of these kinases in the immunosurveillance defects of human serrated CRC. These findings provide insight into avenues for the detection and treatment of this poor-prognosis subtype of CRC. |
DOI | 10.1016/j.immuni.2018.09.013 |
Alternate Journal | Immunity |
PubMed ID | 30552022 |
PubMed Central ID | PMC6301096 |
Grant List | R01 CA192642 / CA / NCI NIH HHS / United States R01 CA218254 / CA / NCI NIH HHS / United States R01 CA172025 / CA / NCI NIH HHS / United States P30 CA030199 / CA / NCI NIH HHS / United States R01 CA207177 / CA / NCI NIH HHS / United States |
Related Lab:
Related Faculty:
Maria Diaz-Meco Conde, Ph.D.