Targeting tumor microenvironment as a treatment strategy for hepatocellular carcinoma

Abstract

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).

SULT2B1-CS-DOCK2 axis regulates effector T-cell exhaustion in HCC microenvironment

“…However, the adaptive immune response is blunted in HCC patients, as indicated by the enrichment of tumor-associated macrophages and exhaustion of tumor-infiltrated lymphocytes (TILs) in HCC 8 . Thus, targeting tumor-associated macrophages or other cell subsets is a hopeful strategy for HCC therapy 9,10 …”

“…In addition, nivolumab, a PD-1 inhibitor, was granted accelerated approval by the US Food and Drug Administration (FDA) for the treatment of patients with advanced HCC previously treated with sorafenib. However, many HCC patients still can not benefit from immune checkpoint inhibitors; 16 mechanically, failures in antigen presentation, an impaired immune microenvironment, and alterations in immune checkpoint molecules and immune-suppressive cells are responsible for heterogeneous responses and resistance 9 . Interestingly, our group recently identified IL-2 inducible T-cell kinase as a potential tumor microenvironment remodeling indicator for HCC 17 .…”

“…[8] Thus, targeting tumor-associated macrophages or other cell subsets is a hopeful strategy for HCC therapy. [9,10] Immune checkpoints, including cytotoxic T-lymphocyteassociated antigen 4 (CTLA4), programmed cell death 1 (PD-1), and T-cell Ig and mucin domain containing-3 (TIM3), prevent the overactivation of effector lymphocytes. HCC and other types of cancers can utilize this physiological mechanism to evade anti-tumor immune responses.…”

“…However, many HCC patients still can not benefit from immune checkpoint inhibitors; [16] mechanically, failures in antigen presentation, an impaired immune microenvironment, and alterations in immune checkpoint molecules and immune-suppressive cells are responsible for heterogeneous responses and resistance. [9] Interestingly, our group recently identified IL-2 inducible T-cell kinase as a potential tumor microenvironment remodeling indicator for HCC. [17] However, the key factors determining effector T-cell infiltration in HCC remain unclear.…”

Tumor microenvironment heterogeneity an important mediator of prostate cancer progression and therapeutic resistance

“…Usually, the orchestrated impact of microenvironmental components on cancer cells is characterized by the different region, and the tumorigenesis is modulated by the regional heterogeneity in the hypoxia, acidity, and cytokines in a tumor environment 19 , 20 . Moreover, the cancer-associated fibroblasts (CAFs) are among the most abundant constituents in the TME, contributing to the malignant phenotype at all levels 21 – 25 . CAFs comprise heterogeneous clusters exerting distinct functions, such as tumor growth, angiogenic process and stromal remodeling, drug resistance, and tumor metastasis 26 .…”