Targeting Tumor Microenvironment As A Treatment Strategy For Hepatocellular Carcinoma

HepatoBiliary Surg Nutr 2020;9(6):794-796 | http://dx.doi.org/10.21037/hbsn.2020.03.24 Liver cancer was ranked the sixth most commonly diagnosed cancer with the fourth leading cause of cancer-related deaths worldwide in 2018 (1). Notably, hepatocellular carcinoma (HCC) constitutes 75–85% among all the liver cancer cases, and ranks first morbidity and mortality of malignancies in Chinese males under 60. Due to hypervascularity in liver and high heterogeneity, HCC was regarded as an aggressive disease. Recent clinical trials focusing on resection and transplantation after targeted therapy for advanced HCC show encouraging results. However, the adjuvant therapy for patients with high risk of recurrence after surgery still raises attention. Currently, emerging evidence suggested that the crosstalk between tumor cells and the microenvironment plays a pivotal role in tumorigenesis and metastasis. The tumor microenvironment of HCC provides tumor cells with necessary conditions for their sustained growth, invasion and metastasis. It is typically characterized by dysregulated immune network, sustained injury and regeneration, angiogenesis, inflammation and metabolic reprogramming. These aforementioned characteristics raise attention to the important role of infiltrating immune cell profile and tumor stroma in microenvironmental regulation. According to the immune cell subset and proportion, HCC could be classified into different immune subtypes, for example, Sia’s “immune class/ exclusion” and Kurebayashi’s “immune high/mid/low”. Zhang et al. further identified three novel distinctive HCC subtypes with immunocompetent, immunodeficient, and immunosuppressive features (2). Immunocompetent and immunosuppressive subtype were characterized by robust immune cell infiltration and upregulated immune checkpoint molecules. These two subtypes, as well as the “immune class” and “immune-high subtype”, displayed significant increase in immune cells infiltration and better responsiveness to immunotherapy. Tumor stroma and vasculature could also cause considerable impact on tumor progression. Cancer-associated fibroblasts (CAFs) can result in a robust stromal reaction characterized by fibrotic extracellular matrix and make tumor cells convert to aggressive and immune-excluded phenotype via transforming growth factor-β (TGF-β) signaling pathway (3). Tumor-associated vasculature is another main hallmark of cancers. Endothelial cells (ECs) of the tumor vasculature can not only inhibit anti-tumor immunity by immune cells regulation and elimination, but also help to create a proangiogenic microenvironment via vascular endothelial growth factor (VEGF) signaling pathway (4). The disorganized tumor vasculature could remodel a special microenvironment characterized by hypoxia, acidosis, and high interstitial pressure, which both support tumor cells proliferation and structure a physical barrier for infiltrating immune cells (5). Furthermore, the interaction between different components relies on the regulation of chemokines and cytokines, which play essential roles in recruiting immune cells and maintaining cancer and stromal cell biology (6). In another word, these microenvironmental populations profoundly influence the tumor immune and metabolic homeostasis, which suggests immunometabolism as a novel perspective of HCC microenvironment. Editorial