Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland.
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
J Immunother Cancer. 2021 Apr;9(4). doi: 10.1136/jitc-2020-002297.
Myeloid cells represent an abundant yet heterogeneous cell population in the colorectal cancer microenvironment, and their roles remain poorly understood.
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.
Higher intraepithelial (=0.0002; HR for Q4 (vs Q1), 0.48, 95% CI 0.31 to 0.76) and stromal ( <0.0001; HR for Q4 (vs Q1), 0.42, 95% CI 0.29 to 0.63) densities of CD14HLA-DR cells were associated with lower colorectal cancer-specific mortality while, conversely, higher intraepithelial densities of CD14HLA-DR cells were associated with higher colorectal cancer-specific mortality (=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 CD14HLA-DR cells were closer to tumor than CD14HLA-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 CD14HLA-DR cell versus CD14HLA-DR cell within a 20 µm radius, was associated with lower colorectal cancer-specific mortality ( <0.0001; HR for Q4 (vs Q1), 0.37, 95% CI 0.24 to 0.57).
Myeloid cell populations occur in spatially distinct distributions and exhibit divergent, subset-specific prognostic significance in colorectal cancer, with mature CD14HLA-DR and immature CD14HLA-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.
髓系细胞是结直肠癌微环境中丰富而异质的细胞群体，但它们的作用仍知之甚少。
我们使用多重免疫荧光结合数字图像分析来鉴定 CD14 单核细胞和 CD15 粒细胞，并评估其成熟度（HLA-DR 和 CD33）、免疫抑制潜力（ARG1）以及与细胞角蛋白（KRT）阳性肿瘤细胞的接近程度，共纳入 913 例结直肠癌患者。利用 2 项前瞻性队列研究中 4465 例结直肠癌患者的协变量数据，采用逆概率加权法和多变量调整的 Cox 比例风险模型，根据髓系细胞密度的四分位数（Q1-Q4）评估癌症特异性死亡率。采用最近邻法和 G 交叉函数来测量免疫细胞-肿瘤细胞的接近程度，该函数确定任何肿瘤细胞在一定半径内至少有一个指定类型的免疫细胞的可能性。
上皮内（=0.0002；Q4 与 Q1 相比，HR 为 0.48，95%CI 为 0.31 至 0.76）和基质内（ <0.0001；Q4 与 Q1 相比，HR 为 0.42，95%CI 为 0.29 至 0.63）CD14HLA-DR 细胞密度较高与结直肠癌特异性死亡率较低相关，而相反，上皮内 CD14HLA-DR 细胞密度较高与结直肠癌特异性死亡率较高相关（=0.0003；Q4 与 Q1 相比，HR 为 1.78，95%CI 为 1.25 至 2.55）。空间分析表明，CD15 细胞比 CD14 细胞更接近肿瘤细胞，而 CD14HLA-DR 细胞比 CD14HLA-DR 细胞更接近肿瘤细胞（p<0.0001）。G 交叉接近度测量评估了任何肿瘤细胞与至少一个 CD14HLA-DR 细胞共定位的可能性与在 20μm 半径内与 CD14HLA-DR 细胞共定位的可能性之间的差异，与结直肠癌特异性死亡率较低相关（ <0.0001；Q4 与 Q1 相比，HR 为 0.37，95%CI 为 0.24 至 0.57）。
髓系细胞群体在空间上存在明显的分布差异，表现出不同的、亚群特异性的结直肠癌预后意义，其中成熟的 CD14HLA-DR 和不成熟的 CD14HLA-DR 单核细胞表型表现出相反的关联。这些结果突出了髓系细胞浸润的多标志物评估的预后效用，并揭示了髓系细胞在免疫微环境中以前未被认识到的空间组织程度。
