Prognostic significance of myeloid immune cells and their spatial distribution in the colorectal cancer microenvironment. Issue 4 (30th April 2021)

• Record Type: Journal Article
• Authors: Väyrynen, Juha P; Haruki, Koichiro; Väyrynen, Sara A; Lau, Mai Chan; Dias Costa, Andressa; Borowsky, Jennifer; Zhao, Melissa; Ugai, Tomotaka; Kishikawa, Junko; Akimoto, Naohiko; Zhong, Rong; Shi, Shanshan; Chang, Tzuu-Wang; Fujiyoshi, Kenji; Arima, Kota; Twombly, Tyler S; Da Silva, Annacarolina; Song, Mingyang; Wu, Kana; Zhang, Xuehong; Chan, Andrew T; Nishihara, Reiko; Fuchs, Charles S; Meyerhardt, Jeffrey A; Giannakis, Marios; Ogino, Shuji; Nowak, Jonathan A
• Is Part Of: Journal for immunotherapy of cancer. Volume 9:Issue 4(2021)
• Publication Date: 2021-04-30
• Subjects: colorectal cancer -- anti-tumor immunity -- myeloid cells -- innate immunity -- spatial analysis -- tumor microenvironment; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2020-002297
• Languages: English
• ISSNs: 2051-1426

Abstract

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 ( P trend =0.0002; HR for Q4 (vs Q1), 0.48, 95% CI 0.31 to 0.76) and stromal ( P trend <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 ( P trend =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 ( P trend <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.