<p>Tumor-Associated CD163⁺ M2 Macrophage Infiltration is Highly Associated with PD-L1 Expression in Cervical Cancer</p>

Abstract

Background: Programmed death-ligand 1 (PD-L1) is a negative costimulatory molecule, and its main function is widely considered to be in the regulation of T cells. Tumorassociated macrophages (TAMs) are an important part of the tumor microenvironment, and they also play an important role in immunosuppression. However, the relationship between the expression of PD-L1 and TAMs in cervical carcinoma (CC) remains unclear. We detected the expression of PD-L1 and TAMs in tumor tissue to study the correlation between them. Methods: Immunohistochemical staining of PD-L1, CD68 (pan-macrophage), and CD163 (M2-like macrophage) was performed in 120 cases of cervical squamous cell carcinoma. Logistic regression analysis was used to evaluate the predictors related to positive PD-L1 expression. We also apply the Kaplan-Meier method to study the recurrence-free and overall survival rate of CC patients. Results: The increase in PD-L1 expression in tumor cells (TC) was significantly correlated with the increase in CD163 density (r=0.8550, p<0.0001), while PD-L1 in the stroma was also significantly associated with the intratumoral density of CD68-or CD163-positive cells (CD68 p<0.0001; CD163 p=0.0009). The mean infiltration rates of CD68-and CD163positive cells in PD-L1-positive TC were significantly higher than in PD-L1-negative TC (CD68 p=0.0095; CD163 p<0.0001). In multivariate logistic regression analyses, only the density of CD163-positive cells was correlated with the expression of PD-L1 in TC cells (OR 1.52; p=0.032). In prognostic analysis, PD-L1 more than 10% was significantly correlated with short RFS (HR=2.66; p=0.028). For CD163 + macrophage evaluation, the density above the median was also significantly correlated with RFS (HR=2.48; p=0.021). Conclusion: CD163 + M2-like macrophage infiltration is highly associated with PD-L1 expression in CC, suggesting that macrophage infiltration can serve as a potential therapeutic target.

TIME Is Ticking for Cervical Cancer

“…Elevated M2 levels in the TIME can create an immunosuppressive environment by supporting the generation and recruitment of myeloid-derived suppressor cells (MDSC) and regulatory T-cells (T regs ) generation and recruitment (Figures 1B and 3) [130,135] while suppressing antitumor cytotoxic NK cells [136]. The increased CD163 + M2 macrophages in the CC TIME are highly associated with overexpression of PD-L1 that supports immunosuppression through T-cell exhaustion and suppresses the PD-1/PD-L1 blockers' efficacy, as discussed previously [137].…”

Spatial Profile of Tumor Microenvironment in PD-L1-Negative and PD-L1-Positive Triple-Negative Breast Cancer

“…All of these cell types were predominant in PD-L1-positive tumors. Interestingly, regarding M2 macrophages, there is evidence that PD-L1 expression not only correlates with the presence of M2 macrophages in the tumor microenvironment [ 13 ] but can also be promoted by this cell type [ 14 ]. It should be noted that the search for similar clusters for PD-L1-negative and PD-L1-positive tumors allowed us to identify significant signatures of macrophages, which dramatically increases the relevance of these cells as possible predictor markers for immunotherapy.…”

M2‐polarization‐related CNTNAP1 gene might be a novel immunotherapeutic target and biomarker for clear cell renal cell carcinoma

“…Our analysis results showed CNTNAP1 was positively correlated with CAFs, Besides, increasing evidence suggest that TAMs might act as a promising oncology target in many malignancies, of which thus being the research focus all over the world currently. 7,[60][61][62] Of note, M2-macrophage [63][64][65] was considered to be an immune-suppressive phenotype while M1-macrophage 66 played a crucial role in killing tumor cells. Another important observation stemming from this study is that CNTNAP1 acted as M2-polarization-related gene.…”