Correlation Between Tumor-Associated Macrophage and Immune Checkpoint Molecule Expression and Its Prognostic Significance in Cutaneous Melanoma.

Woo Jin Lee,Mi Woo Lee,Young Jae Kim,Chong Hyun Won,Jee Ho Choi,Sung Eun Chang

doi:10.3390/jcm9082500

Woo Jin Lee, Mi Woo Lee + Show 4 more

Open Access

https://doi.org/10.3390/jcm9082500

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Abstract

The association between tumor-associated macrophages (TAMs) and the expression of immune checkpoint molecules has not been well described in cutaneous melanoma. We evaluated the correlations between the expression of markers of TAMs, cluster of differentiation 163 (CD163), and immune checkpoint molecules, programmed cell death protein-1 (PD-1), and lymphocyte activating gene-3 (LAG-3). We also determined their relationships with the clinicopathological features and disease outcomes in melanoma. Diagnostic tissues collected from melanoma patients were evaluated using immunohistochemistry for CD163, PD-1, and LAG-3 expression. CD163 expression positively correlated with PD-1 and LAG-3 expression. High expression of both CD163 and PD-1 expressions was significantly associated with negative prognostic factors and worse prognosis than high expression of the single markers. High co-expression of CD163 and LAG-3 was associated with poor clinicopathological indexes of melanoma and worse survival compared to the high expression of the single markers. The expression of immune checkpoint molecules PD-1 and LAG-3 positively correlated with the M2-TAM density in melanoma tissue. Simultaneous high M2-TAM density and immune checkpoint molecules expression acted as independent poor prognostic factors in cutaneous melanoma.

Highlights

Programmed cell death protein-1 (PD-1) is a major inhibitory receptor expressed on T, B, and natural killer (NK) cells and mediating the suppression of antitumor immunity [1]
Among the 53 patients with a high expression of PD-1, 32 (60.4%) patients revealed a high expression of cluster of differentiation 163 (CD163)
There was a significant association between CD163 and both PD-1 expression (p = 0.003) and lymphocyte activating gene-3 (LAG-3) expression (p < 0.001) (Table 2)

Summary

Introduction

Programmed cell death protein-1 (PD-1) is a major inhibitory receptor expressed on T, B, and natural killer (NK) cells and mediating the suppression of antitumor immunity [1]. Programmed cell death protein-1/ligand-1 (PD-1/PD-L1) signaling inhibitors act as representative immunotherapeutic agents that activate anti-tumor immune responses in various tumors [4]. Another emerging immune checkpoint molecule, lymphocyte activating gene-3 (LAG-3), revealed a synergistic immunosuppressive action with PD-1 [5]. CD163-positive M2 macrophages play a role in promoting tumor development by suppressing antitumor immunity [8]. Representative immune cells, such as dendritic cells, neutrophils, and regulatory T cells interact with CD163-positive M2 macrophages [9]

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