University of Oulu

Väyrynen JP, Haruki K, Väyrynen SA, et al Prognostic significance of myeloid immune cells and their spatial distribution in the colorectal cancer microenvironment Journal for ImmunoTherapy of Cancer 2021;9:e002297. doi: 10.1136/jitc-2020-002297

Prognostic significance of myeloid immune cells and their spatial distribution in the colorectal cancer microenvironment

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Author: Väyrynen, Juha P1,2,3; Haruki, Koichiro2,3,4; Väyrynen, Sara A2;
Organizations: 1Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland
2Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
3Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
4Department of Surgery, Jikei University School of Medicine, Tokyo, Japan
5Conjoint Gastroenterology Department, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
6Department of Epidemiology, Harvard University T.H. Chan School of Public Health, Boston, Massachusetts, USA
7Department of Nutrition, Harvard University T.H. Chan School of Public Health, Boston, Massachusetts, USA
8Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
9Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA
10Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
11Department of Immunology and Infectious Diseases, Harvard University T.H. Chan School of Public Health, Boston, Massachusetts, USA
12Department of Biostatistics, Harvard University T.H. Chan School of Public Health, Boston, Massachusetts, USA
13Yale University Yale Cancer Center, New Haven, Connecticut, USA
14Department of Medicine, Yale School of Medicine, New Haven, Connecticut, USA
15Smilow Cancer Hospital, New Haven, Connecticut, USA
16Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
17Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
18Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, Massachusetts, USA
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.1 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2021052131147
Language: English
Published: BMJ, 2021
Publish Date: 2021-05-21
Description:

Abstract

Background: Myeloid cells represent an abundant yet heterogeneous cell population in the colorectal cancer microenvironment, and their roles remain poorly understood.

Methods: We used multiplexed immunofluorescence combined with digital image analysis to identify CD14⁺ monocytic and CD15⁺ granulocytic cells and to evaluate their maturity (HLA-DR and CD33), immunosuppressive potential (ARG1) and proximity to cytokeratin (KRT)-positive tumor cells in 913 colorectal carcinomas. Using covariate data of 4465 incident colorectal cancers in two prospective cohort studies, the inverse probability weighting method was used with multivariable-adjusted Cox proportional hazards models to assess cancer-specific mortality according to ordinal quartiles (Q1–Q4) of myeloid cell densities. Immune cell–tumor cell proximity was measured with the nearest neighbor method and the G-cross function, which determines the likelihood of any tumor cell having at least one immune cell of the specified type within a certain radius.

Results: Higher intraepithelial (Ptrend=0.0002; HR for Q4 (vs Q1), 0.48, 95% CI 0.31 to 0.76) and stromal (Ptrend <0.0001; HR for Q4 (vs Q1), 0.42, 95% CI 0.29 to 0.63) densities of CD14⁺HLA-DR⁺ cells were associated with lower colorectal cancer-specific mortality while, conversely, higher intraepithelial densities of CD14⁺HLA-DR⁻ cells were associated with higher colorectal cancer-specific mortality (Ptrend=0.0003; HR for Q4 (vs Q1), 1.78, 95% CI 1.25 to 2.55). Spatial analyses indicated that CD15⁺ cells were located closer to tumor cells than CD14⁺ cells, and CD14⁺HLA-DR⁺ cells were closer to tumor than CD14⁺HLA-DR⁻ cells (p<0.0001). The G-cross proximity measurement, evaluating the difference in the likelihood of any tumor cell being colocated with at least one CD14⁺HLA-DR⁺ cell versus CD14⁺HLA-DR⁻ cell within a 20 µm radius, was associated with lower colorectal cancer-specific mortality (Ptrend <0.0001; HR for Q4 (vs Q1), 0.37, 95% CI 0.24 to 0.57).

Conclusions: Myeloid cell populations occur in spatially distinct distributions and exhibit divergent, subset-specific prognostic significance in colorectal cancer, with mature CD14⁺HLA-DR⁺ and immature CD14⁺HLA-DR⁻ monocytic phenotypes most notably showing opposite associations. These results highlight the prognostic utility of multimarker evaluation of myeloid cell infiltrates and reveal a previously unrecognized degree of spatial organization for myeloid cells in the immune microenvironment.

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Series: Journal for immunotherapy of cancer
ISSN: 2051-1426
ISSN-E: 2051-1426
ISSN-L: 2051-1426
Volume: 9
Issue: 4
Article number: e002297
DOI: 10.1136/jitc-2020-002297
OADOI: https://oadoi.org/10.1136/jitc-2020-002297
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Subjects:
Funding: This work was supported by US National Institutes of Health (NIH) grants (P01 CA87969 to M J Stampfer; UM1 CA186107 to M J Stampfer; P01 CA55075 to W C Willett; UM1 CA167552 to W C Willett; U01 CA167552 to W C Willett and L A Mucci; P50 CA127003 to CSF; R01 CA118553 to CSF; R01 CA169141 to CSF; R01 CA137178 to ATC; K24 DK098311 to ATC; R35 CA197735 to SO; R01 CA151993 to SO; R01 CA248857 to SO, U Peters, and A I Phipps; K07 CA190673 to RN; R03 CA197879 to KW; R21 CA222940 to KW and MG; R21 CA230873 to KW and SO; and K07 CA188126 to XZ); by Nodal Award (2016-02) from the Dana-Farber Harvard Cancer Center (to SO); by the Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant (SU2C-AACR-DT22-17 to CSF and MG), administered by the American Association for Cancer Research, a scientific partner of SU2C; and by grants from the Project P Fund, The Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. KH was supported by fellowship grants from the Uehara Memorial Foundation and the Mitsukoshi Health and Welfare Foundation. SAV was supported by grants from the Finnish Cultural Foundation and Orion Research Foundation. JB was supported by a grant from the Australia Awards-Endeavour Scholarships and Fellowships Program. KF was supported by a fellowship grant from the Uehara Memorial Foundation. KA was supported by grants from Overseas Research Fellowship from Japan Society for the Promotion of Science (JP201860083). KW was supported by an Investigator Initiated Grant from the American Institute for Cancer Research. ATC is a Stuart and Suzanne Steele MGH Research Scholar. JAM research is supported by the Douglas Gray Woodruff Chair fund, the Guo Shu Shi Fund, Anonymous Family Fund for Innovations in Colorectal Cancer, Project P fund, and the George Stone Family Foundation. MG was supported by a Conquer Cancer Foundation of ASCO Career Development Award.
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