Journal
CANCER IMMUNOLOGY RESEARCH
Volume 9, Issue 1, Pages 8-19Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-20-0527
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Funding
- NIH [P01 CA87969, UM1 CA186107, P01 CA55075, UM1CA167552, U01 CA167552, P50 CA127003, R01 CA118553, R01 CA169141, R01 CA137178, K24 DK098311, R35 CA197735, R01 CA151993, K07 CA190673, R03 CA197879, R21 CA222940, R21 CA230873]
- Cancer Research UK Grand Challenge Award (UK) [C10674/A27140]
- Dana-Farber Harvard Cancer Center [2016-02]
- Project P Fund, The Friends of the Dana-Farber Cancer Institute
- Bennett Family Fund
- Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance
- Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant [SU2C-AACR-DT22-17]
- Uehara Memorial Foundation
- Mitsukoshi Health and Welfare Foundation
- Finnish Cultural Foundation
- Orion Research Foundation
- Australia Awards-Endeavour Scholarships and Fellowships Program
- Overseas Research Fellowship from Japan Society for the Promotion of Science [JP201860083]
- American Institute for CancerResearch (AICR)
- Douglas Gray Woodruff Chair fund
- Anonymous Family Fund for Innovations in Colorectal Cancer
- Project P fund
- George Stone Family Foundation
- Conquer Cancer Foundation of ASCO Career Development Award
- Research Computing Group, at Harvard Medical School
- American Association for Cancer Research, a scientific partner of SU2C
- Guo Shu Shi Fund
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In colorectal cancer, high stromal density of M2-like macrophages is associated with worse cancer-specific survival, while stromal density of M1-like macrophages is not significantly linked to better survival. The ratio of M1 to M2 density in tumor stroma is associated with improved cancer-specific survival.
Macrophages are among the most common cells in the colorectal cancer microenvironment, but their prognostic significance is incompletely understood. Using multiplexed immunofluorescence for CD68, CD86, IRF5, MAF, MRC1 (CD206), and KRT (cytokeratins) combined with digital image analysis and machine learning, we assessed the polarization spectrum of tumor-associated macrophages in 931 colorectal carcinomas. We then applied Cox proportional hazards regression to assess prognostic survival associations of intraepithelial and stromal densities of M1-like and M2-like macrophages while controlling for potential confounders, including stage and microsatellite instability status. We found that high tumor Aromal density of M2-like macrophages was associated with worse cancer-specific survival, whereas tumor stromal density of M1-like macrophages was not significantly associated with better cancer-specific survival. High M1:M2 density ratio in tumor stroma was associated with better cancer-specific survival. Over-all macrophage densities in tumor intraepithelial or stromal regions were not prognostic. These findings suggested that macrophage polarization state, rather than their overall density, was associated with cancer-specific survival, with M1- and M2-like macrophage phenotypes exhibiting distinct prognostic roles. These results highlight the utility of a multimarker strategy to assess the macrophage polarization at single-cell resolution within the tumor microenvironment.
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