Tumor-associated macrophages and CD8+ T cells: dual players in the pathogenesis of HBV-related HCC

Abstract

HBV infection is a key risk factor for the development and progression of hepatocellular carcinoma (HCC), a highly invasive tumor, and is characterized by its persistent immunosuppressive microenvironment. This review provides an in-depth analysis of HBV-related HCC and explores the interactions between neutrophils, natural killer cells, and dendritic cells, examining their roles in regulating tumor-associated macrophages and CD8+ T cells and shaping the tumor microenvironment. Two critical players in the immunosuppressive milieu of HBV-related HCC are CD8+ T cells and tumor-associated macrophages (TAMs). The study explores how TAMs, initially recruited to combat infection, transform, adopting a tumor-promoting phenotype, turning against the body, promoting tumor cell proliferation, suppressing anti-tumor immunity, and assisting in the spread of cancer. Meanwhile, CD8+ T cells, crucial for controlling HBV infection, become dysfunctional and exhausted in response to persistent chronic viral inflammation. The review then dissects how TAMs manipulate this immune response, further depleting CD8+ T cell functions through mechanisms like arginine deprivation and creating hypoxic environments that lead to exhaustion. Finally, it explores the challenges and promising therapeutic avenues that target TAMs and CD8+ T cells, either separately or in combination with antiviral therapy and personalized medicine approaches, offering hope for improved outcomes in HBV-related HCC.

Keywords: CD8+ T cell; HBV-related HCC; TAMs-like macrophage; hepatitis B virus; immunology; pathogenesis.

Figure 1

Shows the intricate interaction among different populations of immune cells in the context of HBV-related HCC. The primary emphasis is tumor-associated macrophages (TAMs) and CD8+ T cells as well as their interactions with other immune cells, such as Neutrophils, Natural killer (NK) cells and Dendritic cells (DCs). The figure is created with BioRender.com.

Figure 2

Shows the development of macrophages in HBV-HCC, showing their diverse origins and the mechanism of M1/M2 polarization, as well as their role in cancer. The figure is created with BioRender.com.

Figure 3

Illustrates the dual nature of CD8+ T cells in the context of HBV-HCC. It is establishing a balance between viral management, anticancer activity, and exhaustion against cancer.

Figure 4

This figure highlights the interplay between TAMs and CD8+ T cells in the TME of HBV-related HCC. TAMs suppress CD8+ T cell function by several mechanisms such as direct and indirect macrophage events, arginine deprivation, and hypoxia.