Tumor-associated mesenchymal stromal cells modulate macrophage phagocytosis in stromal-rich colorectal cancer via PD-1 signaling

Niamh A Leonard; Shania M Corry; Eileen Reidy; Hannah Egan; Grace O'Malley; Kerry Thompson; Emma McDermott; Aoise O'Neill; Norashikin Zakaria; Laurence J Egan; Thomas Ritter; Daniela Loessner; Keara Redmond; Margaret Sheehan; Aoife Canney; Aisling M Hogan; Sean O Hynes; Oliver Treacy; Philip D Dunne; Aideen E Ryan

doi:10.1016/j.isci.2024.110701

Tumor-associated mesenchymal stromal cells modulate macrophage phagocytosis in stromal-rich colorectal cancer via PD-1 signaling

iScience. 2024 Aug 22;27(9):110701. doi: 10.1016/j.isci.2024.110701. eCollection 2024 Sep 20.

Authors

Niamh A Leonard^{1

2

3}, Shania M Corry⁴, Eileen Reidy^{1

2

3

5}, Hannah Egan^{1

2

3}, Grace O'Malley^{1

2

3}, Kerry Thompson⁶, Emma McDermott⁶, Aoise O'Neill^{1

2

3}, Norashikin Zakaria^{1

3}, Laurence J Egan^{1

3}, Thomas Ritter^{2

5}, Daniela Loessner^{7

8

9}, Keara Redmond⁴, Margaret Sheehan¹⁰, Aoife Canney¹⁰, Aisling M Hogan^{3

11}, Sean O Hynes^{10

12}, Oliver Treacy^{1

2

3}, Philip D Dunne^{4

13}, Aideen E Ryan^{1

2

3

5}

Affiliations

¹ Discipline of Pharmacology and Therapeutics, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland.
² Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine Nursing and Health Sciences, University of Galway, Galway, Ireland.
³ Lambe Institute for Translational Research, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland.
⁴ Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland.
⁵ CÚRAM Centre for Research in Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland.
⁶ Centre for Microscopy and Imaging, Discipline of Anatomy, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland.
⁷ Barts Cancer Institute, Queen Mary University of London, London, UK.
⁸ Faculty of Engineering and Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia.
⁹ Leibniz-Institut für Polymerforschung Dresden, Dresden, Germany.
¹⁰ Division of Anatomical Pathology, Galway University Hospital, Galway, Ireland.
¹¹ Department of Colorectal Surgery, Galway University Hospital, Galway, Ireland.
¹² Discipline of Pathology, School of Medicine, College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland.
¹³ Cancer Research UK Beatson Institute, Glasgow, UK.

Abstract

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 in vitro, in vivo, and ex vivo 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.

Keywords: Cancer; Immunology; Transcriptomics.