University of Oulu

Väyrynen, J. P., Haruki, K., Lau, M. C., Väyrynen, S. A., Ugai, T., Akimoto, N., Zhong, R., Zhao, M., Dias Costa, A., Borowsky, J., Bell, P., Takashima, Y., Fujiyoshi, K., Arima, K., Kishikawa, J., Shi, S., Twombly, T. S., Song, M., Wu, K., … Nowak, J. A. (2021). Spatial organization and prognostic significance of nk and nkt-like cells via multimarker analysis of the colorectal cancer microenvironment. Cancer Immunology Research, canimm;2326-6066.CIR-21-0772v2. https://doi.org/10.1158/2326-6066.CIR-21-0772

Spatial organization and prognostic significance of NK and NKT-like cells via multimarker analysis of the colorectal cancer microenvironment

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Author: Väyrynen, Juha P.1,2,3; Haruki, Koichiro1,2,4; Lau, Mai Chan2;
Organizations: 1Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
2Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
3Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland
4Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
5Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
6Conjoint Gastroenterology Department, QIMR Berghofer Medical Research Institute, Queensland, Australia
7Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
8Clinical and Trans- lational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
9Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts
10Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
11Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
12Yale Cancer Center, New Haven, Connecticut
13Department of Medicine, Yale School of Medicine, New Haven, Connecticut
14Smilow Cancer Hospital, New Haven, Connecticut
15Genentech, South San Francisco, California
16Broad Institute of MIT and Harvard, Cambridge, Massachusetts
17Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
18Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, Massachusetts
Format: article
Version: accepted version
Access: embargoed
Persistent link: http://urn.fi/urn:nbn:fi-fe202201199473
Language: English
Published: American Association for Cancer Research, 2022
Publish Date: 2023-01-07
Description:

Abstract

Although tumor-infiltrating T cells hold a beneficial prognostic role in colorectal cancer, other lymphocytic populations are less characterized. We developed a multiplexed immunofluorescence assay coupled with digital image analysis and machine learning to identify natural killer (NK) cells (NCAM1+CD3⁻), natural killer T-like (NKT-like) cells (NCAM1⁺CD3⁺), and T cells (NCAM1⁻CD3⁺) within the PTPRC⁺ (CD45⁺) cell population and to measure their granzyme B (GZMB; cytotoxicity marker) and FCGR3A (CD16a; NK-cell maturity marker) expression. We evaluated immune cell densities and spatial configuration in 907 incident colorectal carcinoma cases within two prospective cohort studies. We found that T cells were approximately 100 times more abundant than NK and NKT-like cells. Overall, NK cells showed high GZMB expression and were located closer to tumor cells than T and NKT-like cells. In T and NKT-like cells, GZMB expression was enriched in cells in closer proximity to tumor cells. Higher densities of both T and NKT-like cells associated with longer cancer-specific survival, independent of potential confounders (Ptrend < 0.0007). Higher stromal GZMB+ and FCGR3A+ NK-cell densities associated with longer cancer-specific survival (Ptrend < 0.003). For T and NKT-like cells, greater proximity to tumor cells associated with longer cancer-specific survival (Ptrend < 0.0001). These findings indicate that cytotoxic NCAM1⁺CD3⁻GZMB⁺ NK cells and NCAM1vCD3v NKT-like cells are relatively rare lymphocytic populations within the colorectal cancer microenvironment and show distinct spatial configuration and associations with patient outcome. The results highlight the utility of a quantitative multimarker assay for in situ, single-cell immune biomarker evaluation and underscore the importance of spatial context for tumor microenvironment characterization.

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Series: Cancer immunology research
ISSN: 2326-6066
ISSN-E: 2326-6074
ISSN-L: 2326-6066
DOI: 10.1158/2326-6066.CIR-21-0772
OADOI: https://oadoi.org/10.1158/2326-6066.CIR-21-0772
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Subjects:
Funding: This work was supported by U.S. 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 C.S. Fuchs; R01 CA118553, to C.S. Fuchs; R01 CA169141, to C.S. Fuchs; R01 CA137178, to A.T. Chan; K24 DK098311, to A.T. Chan; R35 CA197735, to S. Ogino; R01 CA151993, to S. Ogino; R01 CA248857, to S. Ogino, U. Peters, and A.I. Phipps; R03 CA197879, to K. Wu; R21 CA222940, to K. Wu and M. Giannakis.; R21 CA230873, to K. Wu and S. Ogino; and K07 CA188126 to X. Zhang); by Nodal Award (2016-02) from the Dana-Farber Harvard Cancer Center (to S. Ogino); by the Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant (SU2C-AACR-DT22-17, to C.S. Fuchs and M. Giannakis), by grants from the Project P Fund, The Friends of the Dana Farber Cancer Institute, the Bennett Family Fund, and the Entertainment Industry Foundation through National Colorectal Cancer Research Alliance. Stand Up To Cancer is a division of the Entertainment Industry Foundation. The indicated SU2C research grant is administered by the American Association for Cancer Research, scientific partner of SU2C. K. Haruki was supported by fellowship grants from the Uehara Memorial Foundation and the Mitsukoshi Health and Welfare Foundation. S.A. V€ayrynen was supported by grants from the Finnish Cultural Foundation and Orion Research Foundation. J. Borowsky was supported by a grant from the Australia Awards-Endeavour Scholarships and Fellowships Program. K. Fujiyoshi was supported by a fellowship grant from the Uehara Memorial Foundation. K. Arima was supported by grants from Overseas Research Fellowship from the Japan Society for the Promotion of Science (JP201860083). K. Wu was supported by an Investigator Initiated Grant from the American Institute for Cancer Research (AICR). A.T. Chan is a Stuart and Suzanne Steele MGH Research Scholar. J.A. Meyerhardt 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. M. Giannakis was supported by a Conquer Cancer Foundation of ASCO Career Development Award. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article.
Copyright information: © 2021 American Association for Cancer Research.