Background
There are a variety of immune cells in the tumor microenvironment, including innate immune cells and adaptive immune cells. Numerous studies have shown that these immune cells interact with cancer cells in complex ways [
1]. In cancer involving tissues of the digestive system, the levels of macrophages, activated mast cells, and CD4+ memory activated T cells may be higher than in normal tissues [
2]. Mast cell infiltration is associated with increased Annexin A1 expression in triple-negative breast cancer [
3]. Programmed cell death 1 (PD-1) blockade is effective in immunotherapy of various tumors, but may cause hyperprogressive disease in immunotherapy of advanced gastric cancer [
4]. In addition, several studies have been published examining the application of immunotherapy based on the function of immune cells in the tumor microenvironment [
5].
Studies have also focused on the relationship between the clinical features, prognosis, and immune therapy of colorectal cancer (CRC) patients and immune cell infiltration of T lymphocytes [
6,
7], Programmed death-ligand 1(PD-L1) [
8], and CD20+ B lymphocytes [
9]. It has also been shown that the infiltration of tumor-associated macrophages (TAMs) is associated with metastasis of CRC [
10], and macrophage-derived IL-6 is associated with drug resistance of CRC [
11].
Macrophages in the tumor microenvironment are divided into M1 and M2 macrophages [
12]. Activated M1 macrophages promote anti-tumor immune responses by regulating antigen presentation and secreting pro-inflammatory cytokines [
13]. M2 macrophages promote tumor development by producing anti-inflammatory cytokines [
14]. The purpose of this study was to evaluate the relationship between the infiltration of CD163+ TAMs and the clinical features and prognosis of CRC patients.
Discussion
In this study, we evaluated the effects of CD163+ TAM infiltration in CRC tissues on the prognosis of CRC patients. The results suggested that CRC patients with high-level TAM infiltration in CRC tissues had worse prognosis than patients with low-level TAM infiltration. COX regression analysis further demonstrated that the infiltration of CD163+ TAMs in CRC tissues was an independent risk factor for the prognosis of CRC patients, and high-level TAM infiltration in CRC tissues was associated with poorer OS and DFS. In addition, serum levels of CEA also associated with DFS in CRC patients.
The prognosis and metastasis of cancer are related to many factors in the tumor microenvironment, including immune cell infiltration [
18], cytokine release [
19], protein expression [
20], and the interaction between different factors [
21,
22]. Experimental studies have shown that high-density TAMs in tumor tissues are associated with low survival rates of breast cancer [
23], liver cancer [
24], and bladder cancer [
25]. However, the relationship between TAM infiltration and the prognosis of CRC patients is still uncertain [
26]. Our results revealed that high-level CD163+ TAM infiltration is associated with poor prognosis of CRC patients, which is consistent with the results of Herrera et al. [
27]. However, a meta-analysis showed that CD163+ TAM infiltration is independent of the 5-year OS in CRC patients [
28], which is inconsistent with the results of this study. This may be related to the different population and having received chemotherapy before surgery.
TAMs are distributed in different microanatomical locations of CRC tissues, such as the center of the tumor and the invasive front of the tumor. TAMs at different locations may include variations in different biological and prognostic characteristics. Wei et al. proposed that an increase in CD163+ TAM infiltration at the invasive front of the tumor is significantly related to the poor prognosis of CRC patients and may play a role in promoting the spread and invasion of CRC [
10]. Algars et al
. showed that the interstitial infiltration of CD163+ TAMs in CRC tissues was associated with a significant increase in survival rates and may exert an anti-tumor role [
29]. In contrast, Shabo et al. determined that the density of macrophages in the tumor stroma was related to poor survival [
30]. Unfortunately, our study could not distinguish between different areas of the CRC tissue, which could have contributed to the impact and robustness of our results. In addition, in our study, data relative to tumor size and tumor deposits were unavailable and thus we could not perform a relevant analysis.
Furthermore, COX regression analysis showed that the infiltration of CD163+ TAMs was an independent prognostic factor for CRC patients and a risk factor for death and recurrence. The surface antigen CD163 is used for the identification of M2 macrophages, which are considered “bad” macrophages because they participate in Th2 immune response and can release anti-inflammatory cytokines able to promote tumor development [
14], although there is evidence that CD163 is not a M2-specific marker [
31]. Therefore, whether the relationship between highly infiltrating CD163+ TAMs and poor prognosis of CRC is due to M2 cells is still uncertain, and further research is needed to provide more definitive evidence.
Conclusions
In summary, our study demonstrates that infiltration of CD163+ TAMs is an independent prognostic factor in patients with CRC. High levels of CD163+ TAM infiltration in CRC tissues is predictive of shorter OS and DFS, which has guiding significance for the prognosis and postoperative treatment of CRC patients undergoing resection surgery.
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