Tumor-associated mesenchymal stromal cells modulate macrophage phagocytosis in stromal-rich colorectal cancer via PD-1 signaling
CMS4 colorectal cancer (CRC), based on the consensus molecular subtype (CMS), stratifies patients with the poorest disease-free survival rates. It is characterized by a strong mesenchymal stromal cell (MSC) signature, wound healing-like inflammation and therapy resistance. We utilized 2D and 3D <i>in vitro, in vivo</i>, and <i>ex vivo</i> models to assess the impact of inflammation and stromal cells on immunosuppression in CMS4 CRC. RNA sequencing data from untreated stage II/III CRC patients showed enriched TNF-α signatures in CMS1 and CMS4 tumors. Secretome from TNF-α treated cancer cells induced an immunomodulatory and chemotactic phenotype in MSC and cancer-associated fibroblasts (CAFs). Macrophages in CRC tumours migrate and preferentially localise in stromal compartment. Inflammatory CRC secretome enhances expression of PD-L1 and CD47 on both human and murine stromal cells. We demonstrate that TNF-α-induced inflammation in CRC suppresses macrophage phagocytosis via stromal cells. We show that stromal cell-mediated suppression of macrophage phagocytosis is mediated in part through PD-1 signaling. These data suggest that re-stratification of CRC by CMS may reveal patient subsets with microsatellite stable tumors, particularly CMS4-like tumors, that may respond to immunotherapies.
Authors
- Grace O’Malley
- Daniela Loessner (ORCID: https://orcid.org/0000-0001-5891-3441)
- Kerry Thompson (ORCID: https://orcid.org/0000-0003-2721-8977)
- Aideen E. Ryan (ORCID: https://orcid.org/0000-0002-5831-6783)
- Aisling Hogan (ORCID: https://orcid.org/0000-0002-8166-732X)
- Norashikin Zakaria (ORCID: https://orcid.org/0000-0003-2589-1543)
- Oliver Treacy (ORCID: https://orcid.org/0000-0003-3898-9806)
- Eileen Reidy (ORCID: https://orcid.org/0000-0001-5562-5241)
- Aoife Canney
- Mary C. Sheehan (ORCID: https://orcid.org/0000-0002-2070-4094)
- Seán O. Hynes (ORCID: https://orcid.org/0000-0002-3092-7945)
- Niamh Leonard (ORCID: https://orcid.org/0000-0002-8438-1765)
- Philip D. Dunne (ORCID: https://orcid.org/0000-0001-9160-283X)
- Thomas Ritter (ORCID: https://orcid.org/0000-0001-7709-8489)
- Laurence John Egan (ORCID: https://orcid.org/0000-0002-0142-6340)
- Shania M. Corry
- Emma McDermott (ORCID: https://orcid.org/0000-0001-8149-6164)
- Hannah Egan
- Keara L. Redmond
- Aoise O’Neill
Institutions
- Queen Mary University of London (GB)
- Ollscoil na Gaillimhe – University of Galway (IE)
- University Hospital Galway (IE)
- Leibniz Institute of Polymer Research (DE)
- Monash Health (AU)
- Regenerative Medicine Institute (MX)
- Cancer Research UK Scotland Institute (GB)
- Monash University (AU)
Publication Details
- Journal
- iScience
- Published
- 2024-08-23
- DOI
- https://doi.org/10.1016/j.isci.2024.110701
- Citations
- 16
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 4.52
Funders
- UK Research and Innovation
- Cancer Research UK
- Science Foundation Ireland
- University of Galway
- Servier
- Galway University Foundation
- Engineering and Physical Sciences Research Council
- European Regional Development Fund