Prognostic significance of the infiltration of CD163⁺ macrophages combined with CD66b⁺ neutrophils in gastric cancer

Abstract

The polarization of tumor‐associated macrophages (TAMs) and tumor‐associated neutrophils (TANs), especially from the antitumoral phenotype to the protumoral phenotype under certain conditions, has an important influence on the progression of tumors. However, the interactions and combined prognosis of these cells are poorly known. Here, we detected the infiltration of CD68+ TAMs, CD163+ TAMs, and CD66b+ TANs in the specimens from 662 patients with GC by immunohistochemistry. The results showed that the infiltration of each of CD163+, CD68+, and CD66b+ cells in GC tissue was significantly increased and independently associated with GC prognosis. Strong collinearity (r = 0.690, P < 0.001) was found between the infiltration of CD163+ and CD68+ cells in GC, and multivariate Cox analysis confirmed the infiltration of CD163+ cells was a better predictor for prognosis than that of CD68+ cells. The combination of the infiltration of CD163+ and CD66b+ cells provided more accurate survival prediction than any individual marker. Patient subgroups with CD66blowCD163low (hazard ratio (HR) = 2.161; 95% confidence interval (CI) = 1.266–3.688; P < 0.001), CD66bhighCD163high (HR = 3.575; 95% CI = 2.155–5.933; P < 0.001), and CD66blowCD163high (HR = 7.514; 95% CI = 4.583–12.312; P < 0.001) were gradually associated with shorter DFS when compared with the subgroup with CD66bhighCD163low. The similar result was also for DSS among the subgroups. Moreover, the two‐marker model could more effectively discriminate the prognosis among the patients with chemotherapy than that among those without chemotherapy. We concluded that CD163+ TAMs were a more valuable prognostic marker than CD68+ TAMs, and CD163+ TAMs combined with CD66b+ TANs could more precisely predict the prognosis of patients with GC.

Intratumoral Immune Response to Gastric Cancer Varies by Molecular and Histologic Subtype

“…Phenotypic profiling of cell surface markers revealed mixed expression of stimulatory M1-like markers (MHC class II/HLA-DR) and inhibitory M2-like markers (CD163 scavenger receptor, matrix metalloproteinase MMP9), with a trend toward increased inhibitory marker expression in intestinal-type tumors. Limited studies of gastric cancer-associated macrophages in the literature report similar phenotypic heterogeneity (25), and variable association with survival (25,26). One functional report of macrophages isolated from freshly resected human gastric cancers identified an inhibitory effect on tumor-infiltrating natural killer (NK) cells, mediated by the cytokine TGF-beta (27).…”

Sexual dimorphism in gastric cancer: tumor-associated neutrophils predict patient outcome only for women

“…The TAN density at the invasion front (HR 2.77; 95% CI 1.64-4.77) of women with GC was an independent predictor of favorable patient outcome and even surpassed MSI status (Table 3). Interestingly, studies on TANs in Asian cohorts were unable to find any sex-specific differences (Fu et al 2016;Huang et al 2018;Li et al 2017;Zhang et al 2018;Zhao et al 2012). However, tumor immunity signatures differ significantly between Asian and non-Asian GC patients, including markers of TANs (i.e., CD66b) and may contribute to differences in clinical outcome (Lin et al 2015).…”

“…Different from previous attempts on the exploitation of TANs in GC using selected high-power fields (Caruso et al 2002;Li et al 2017;Zhao et al 2012) or tissue micro arrays (Huang et al 2018), we were specifically interested in the spatial distribution of TANs in GC by using digital image analysis on whole tissue sections and well-defined tumor areas, limiting the risk of observer bias. We found significant differences in the TAN densities with regard to their spatial distribution (tumor surface vs. tumor center vs. invasion front).…”

“…In the past, a limited number of studies provided evidence that TANs may also be involved in GC biology, showing divergent results with regard to the protective (Abe et al 2016;Caruso et al 2002;Huang et al 2018;Zhang et al 2018) or promoting effects (Li et al 2017;Wang et al 2017;Zhao et al 2012) of TANs. Only a single study was carried out on Western patients, which, interestingly, showed evidence of a sex-dependent effect (Caruso et al 2002) pointing towards sexual dimorphism.…”

Preliminary analysis of single-nucleotide polymorphisms in IL-10, IL-4, and IL-4Rα genes and profile of circulating cytokines in patients with gastric Cancer

“…Therefore, the findings in this research could confer relevance to determining this immunological marker in individuals at risk of developing neoplasm, like gastric cancer, in support of our initial hypothesis of a possible environment modulated by IL-4 and M2 cells in patients (whose specific evidence was not within the scope of this study), given that the finding of infiltrating or tumour-associated macrophages (TAMs) in the tumor microenvironment has been associated to poor prognosis [ 17 , 18 ], evidenced in several neoplasms affecting kidneys, ovaries, endometrium, breasts, lungs, skin [ 47 – 53 ], as well as pancreas, esophageal squamous cell carcinoma [ 54 ] and aggressive gastric carcinoma, in relation to a greater stage and poor tumor differentiation [ 55 , 56 ] although its prognostic role may vary according to the type of tumour [ 57 ].…”