Prognostic significance of myeloid immune cells and their spatial distribution in the colorectal cancer microenvironment.
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| 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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| Authors | Juha P Väyrynen, Koichiro Haruki, Sara A Väyrynen, Mai Chan Lau, Andressa Dias Costa, Jennifer Borowsky, Melissa Zhao, Tomotaka Ugai, Junko Kishikawa, Naohiko Akimoto, Rong Zhong, Shanshan Shi, Tzuu-Wang Chang, Kenji Fujiyoshi, Kota Arima, Tyler S Twombly, Annacarolina Da Silva, Mingyang Song, Kana Wu, Xuehong Zhang, Andrew T Chan, Reiko Nishihara, Charles S Fuchs, Jeffrey A Meyerhardt, Marios Giannakis, Shuji Ogino, Jonathan A Nowak |
| Journal | Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 9 Issue 4 (04 2021) ISSN: 2051-1426 [Electronic] England |
| PMID | 33931472 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't) |
| Copyright | © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. |
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