Resistance of MMTV-NeuT/ATTAC mice to anti-PD-1 immune checkpoint therapy is associated with macrophage infiltration and Wnt pathway expression

Hongyan Yuan, Lu Jin, Handan Xiang, Anannya Bhattacharya, Philip E. Brandish, Gretchen Baltus, Alexander Tong, Changyan Zhou, Robert I. Glazer

Research output: Contribution to journalArticlepeer-review

Abstract

One of the central challenges for cancer therapy is the identification of factors in the tumor microenvironment that increase tumor progression and immune tolerance. In breast cancer, fibrosis is a histopathologic criterion for invasive cancer and poor survival that results from inflammatory factors and remodeling of the extracellular matrix to produce an immune tolerant microenvironment. To determine whether tolerance is associated with the immune checkpoint, Programmed Cell Death 1 (PD-1), NeuT/ATTAC mice, a conditional model of mammary fibrosis that we recently developed, were administered a murine-specific anti-PD-1 mAb related to pembrolizumab, and drug response was monitored by tumor development, imaging mass cytometry, immunohistochemistry and tumor gene expression by RNAseq. Tumor progression in NeuT/ATTAC mice was unaffected by weekly injection of anti-PD-1 over four months. Insensitivity to anti-PD-1 was associated with several processes, including increased tumor-associated macrophages (TAM), epithelial to mesenchymal transition (EMT), fibroblast proliferation, an enhanced extracellular matrix and the Wnt signaling pathway, including increased expression of Fzd5, Wnt5a, Vimentin, Mmp3, Col2a1 and Tgfβ1. These results suggest potential therapeutic avenues that may enhance PD-1 immune checkpoint sensitivity, including the use of tumor microenvironment targeted agents and Wnt pathway inhibitors.

Original languageEnglish (US)
Pages (from-to)1350-1358
Number of pages9
JournalOncotarget
Volume13
Issue number1
DOIs
StatePublished - 2022
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by a contract from the Research Institute of Merck and Co., Inc., Rahway, NJ, USA to R.I.G. and award 1P30 CA051008 from the National Cancer Institute, NIH, to the Lombardi Comprehensive Cancer Center. This investigation was conducted using the Animal Research, Genomics and Epigenomics, Histology and Tissue, Flow Cytometry and Microscopy and Imaging Shared Resources of Georgetown University, and by an animal facilities construction grant from the NIH.

Publisher Copyright:
© 2022 Yuan et al.

Keywords

  • NeuT
  • PD-1
  • Wnt
  • macrophages
  • mammary tumorigenesis

PubMed: MeSH publication types

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

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