Infiltration of diametrically polarized macrophages predicts overall survival of patients with gastric cancer after surgical resection

Abstract

Background Tumor-associated macrophages (TAMs), the most predominant tumor-infiltrating immune cells, are emerging prognostic factors and therapeutic targets for personalized therapy against malignant neoplasms. We aimed to evaluate the prognostic significance of diametrically polarized TAMs in gastric cancer and generate a predictive nomogram to refine a risk stratification system. Methods We evaluated polarized functional status of infiltrated TAMs by immunohistochemical staining of CD68, CD11c, and CD206 in 180 consecutive gastric cancer patients from Zhongshan Hospital, Shanghai, China. Prognostic values were assessed in these patients. We created a predictive nomogram by integrating polarized TAMs with the TNM staging system for overall survival of gastric cancer patients.Results CD68 ? TAMs display polarized programs comprising CD11c ? proinflammatory macrophages (M1) and CD206 ? immunosuppressive macrophages (M2) that configure versatile infiltration files in gastric cancer. CD11c ? TAMs negatively correlated with lymph node metastasis (p = 0.012), whereas CD206 ? TAMs correlated with the Lauren classification (p = 0.031). No prognostic difference was observed for overall survival for CD68 density (high vs low, p = 0.1031), whereas high versus low CD11c density (p \ 0.0001) and low vs high CD206 density (p = 0.0105) indicate better overall survival. Multivariate Cox regression analysis identified CD11c and CD206 as independent prognostic factors (p \ 0.001 and p = 0.030, respectively), which could be integrated with the TNM staging system to generate a predictive nomogram for patient outcomes. Conclusion Infiltration of polarized TAMs, a novel identified independent prognostic factor, could be combined with the TNM stage to refine a risk stratification system and better stratify patients with different prognosis. Tipping TAMs to an antitumoral phenotype might be a promising therapeutic target for postoperative treatment.

Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers

“…Up to date, this task has been accomplished using CD11c or NOS2 for M1 TAMs, and CD163, CD204, or CD206 for M2 TAMs. Indeed, increased M1 TAM densities seem to be associated with a favorable clinical outcome in NSCLC (Ma et al, 2010;Ohri et al, 2009), ovarian , colorectal (Edin et al, 2012), and gastric cancer (Zhang, Wang, et al, 2014a), while those of M2 are linked to poor prognosis in several tumors, including NSCLC (Hirayama et al, 2012;Ohtaki et al, 2010;Zeni et al, 2007), mesothelioma (Cornelissen et al, 2014), esophageal (Shigeoka et al, 2013), gastric cancer (Kawahara et al, 2010;Pantano et al, 2013), pancreatic (Hou et al, 2014;Ino et al, 2013;Kurahara et al, 2011;Sugimoto et al, 2014;Sugimura et al, 2015;Zeng et al, 2014), CRC (Herrera et al, 2013), HCC (Kong et al, 2013), Hodgkin lymphoma , renal (Dannenmann et al, 2013;Komohara et al, 2011;Xu et al, 2014), urothelial (Ichimura et al, 2014), breast (Medrek et al, 2012), endometrial (Kübler et al, 2014), ovarian (Lan et al, 2013), melanoma ( Jensen et al, 2009), and squamous oral carcinoma . Additionally, some studies have demonstrated that, when associated with poor clinical outcome, CD68 + cells are often correlated with the tumor microvessel density, in addition to HIF, VEGF (Chai et al, 2008), and matrix metalloproteinase expression (Bolat et al, 2006;Hanada et al, 2000;Leek et al, 1996;Osinsky et al, 2011;Valković et al, 2002), suggesting that they might have an ...…”

Tumor-associated macrophages: Co-conspirators and orchestrators of immune suppression in endometrial adenocarcinoma

“…The presence of TAMs correlates with poor prognosis in several different cancer types [8][9][10][11][12][13]. For example intratumoral TAM density is significantly increased in higher stage and grade in ovarian cancer [14].…”

Reduction in Peripheral CD19+CD24hCD27+ B Cell Frequency Predicts Favourable Clinical Course in XELOX-Treated Patients with Advanced Gastric Cancer

“…In gastric cancer patients, intratumoural infiltrations of cytotoxic T cells and memory cells were shown to indicate better prognoses and survival outcomes [17], while patients with higher tumour-associated microphage (TAM) infiltration had worse surgical outcomes [18,19]. Maskey et al assessed the immune response in gastric cancer patients after neoadjuvant chemotherapy (NACT) and found that those with a low expression of B7-H4 in their tumours had significantly longer OS [20].…”