Hyaluronan driven by epithelial aPKC deficiency remodels the microenvironment and creates a vulnerability in mesenchymal colorectal cancer

Cancer Cell. 2023 Feb 13;41(2):252-271.e9. doi: 10.1016/j.ccell.2022.11.016. Epub 2022 Dec 15.

Abstract

Mesenchymal colorectal cancer (mCRC) is microsatellite stable (MSS), highly desmoplastic, with CD8+ T cells excluded to the stromal periphery, resistant to immunotherapy, and driven by low levels of the atypical protein kinase Cs (aPKCs) in the intestinal epithelium. We show here that a salient feature of these tumors is the accumulation of hyaluronan (HA) which, along with reduced aPKC levels, predicts poor survival. HA promotes epithelial heterogeneity and the emergence of a tumor fetal metaplastic cell (TFMC) population endowed with invasive cancer features through a network of interactions with activated fibroblasts. TFMCs are sensitive to HA deposition, and their metaplastic markers have prognostic value. We demonstrate that in vivo HA degradation with a clinical dose of hyaluronidase impairs mCRC tumorigenesis and liver metastasis and enables immune checkpoint blockade therapy by promoting the recruitment of B and CD8+ T cells, including a proportion with resident memory features, and by blocking immunosuppression.

Keywords: aPKC; colorectal cancer; hyaluronan; immune checkpoint therapy; immunosuppression; inflammation; liver metastasis; mesenchymal; stroma; tumor microenvironment.

Publication types

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

MeSH terms

  • CD8-Positive T-Lymphocytes / pathology
  • Colorectal Neoplasms* / pathology
  • Humans
  • Hyaluronic Acid* / metabolism
  • Immunotherapy
  • Sarcoma / pathology
  • Tumor Microenvironment* / physiology

Substances

  • Hyaluronic Acid