Simultaneous Loss of Both Atypical Protein Kinase C Genes in the Intestinal Epithelium Drives Serrated Intestinal Cancer by Impairing Immunosurveillance

Immunity. 2018 Dec 18;49(6):1132-1147.e7. doi: 10.1016/j.immuni.2018.09.013. Epub 2018 Dec 11.

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.

Keywords: PKCζ; PKCλ/ι; TGF-β; atypical PKCs; colorectal cancer; immunosuppression; immunosurveillance; interferon; intestinal inflammation; serrated adenocarcinoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / immunology
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / metabolism
  • Female
  • Humans
  • Immunologic Surveillance / genetics
  • Immunologic Surveillance / immunology
  • Intestinal Mucosa / enzymology
  • Intestinal Mucosa / immunology*
  • Intestinal Mucosa / pathology
  • Intestinal Neoplasms / enzymology
  • Intestinal Neoplasms / genetics
  • Intestinal Neoplasms / immunology*
  • Isoenzymes / genetics
  • Isoenzymes / immunology*
  • Isoenzymes / metabolism
  • Male
  • Mice, Knockout
  • Mice, Transgenic
  • Middle Aged
  • Protein Kinase C / genetics
  • Protein Kinase C / immunology*
  • Protein Kinase C / metabolism
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • Isoenzymes
  • Receptors, Transforming Growth Factor beta
  • protein kinase C zeta
  • Protein Kinase C
  • protein kinase C lambda