Functional and Clinical Characterization of Tumor-Infiltrating T Cell Subpopulations in Hepatocellular Carcinoma

Abstract

Tumor-infiltrating T-lymphocytes are defined as T-lymphocytes that infiltrated into tumor tissues; however, their composition, clinical significance, and underlying mechanism in hepatocellular carcinoma (HCC) and adjacent non-tumor tissues are still not completely understood. Herein, we collected marker genes of T cell subpopulations from a previous study and estimated their relative infiltrating levels in HCC and adjacent non-tumor tissues. Specifically, the infiltrating levels of all the T cells were significantly reduced in HCC as compared with non-tumor tissues. Unsupervised clustering of the HCC samples by the T cell infiltrating levels revealed that the HCC samples could be clearly classified into two groups. The driver genes, including PTK2B , ATM , PIK3C2B , and KIT , and several CNAs were observed to be associated with reduced T cell infiltrating levels. Particularly, deletion of TP53 more frequently occurred in low T cell infiltration HCC samples and resulted in its downregulation and cell cycle progression, indicating that cell cycle progression was closely associated with reduced T cell infiltration. In contrast, for the samples with high infiltration T cells, its immune evasion might be regulated by the immune checkpoint regulators, such as PD-1/PD-L1 and CTLA4. Moreover, Olaparib, one of the PARP inhibitors, and immune checkpoint inhibitors might be therapeutic candidates for the samples from the two T cell infiltrating clusters. Clinically, the tumor-infiltrating levels of cytotoxic CD4 cell, Mucosal associated invariant T (MAIT) cell, and exhausted CD8 + T cell might be used as predictors for vascular invasion, recurrence, and overall survival. Collectively, we systematically evaluated the clinical significance and potential molecular mechanisms of tumor-infiltrating T cell subpopulations in hepatocellular carcinoma, which might broaden our insights into the immunological features of HCC and provide potential immunotherapeutic targets.

Metabolic rearrangements and intratumoral heterogeneity for immune response in hepatocellular carcinoma

“…It has been reported that CD4+ T-cell apoptosis, which can be induced by linoleic acid, which enhances the expression of carnitine palmitoyl transferase (CPT), accelerates the development of HCC (70). Other reports also confirm the inhibitory significance of CD4+ T cells in carcinogenesis and suggest that the presence of these cells is an independent prognostic marker in HCC (71,72). These multiple features of T cells and their secretions significantly contribute to immunological ITH in HCC.…”

Reprogramming the tumor microenvironment with biotechnology

“…Sakuishi et al observed that only PD-1 expression represents T cell exhaustion imperfectly, but the combination of PD-1 and Tim-3 expression functions as a more accurate marker [ 89 ]. Indeed, targeting the Tim-3-Tim-3L and PD-1-PD-L1 pathways can promote a more effective therapeutic strategy in chronic conditions and TMEs [ 92 , 93 ]. Hung et al observed that reprogramming the methionine metabolism of tumors can inhibit T cell exhaustion [ 94 ].…”

“…The tumor infiltrating T cells play essential roles in tumor immunity. The infiltration of T cells is regulated by immune checkpoints, such as CTLA-4, PD-1, and PD-L1 [93]. Significant infiltration of T cells converts "cold tumor" into "hot tumor", which is related to the effects of immune checkpoint inhibitors and is considered a biomarker to determine the degree of T cell infiltration or activation [100][101][102].…”

Persistent deficiency of mucosa-associated invariant T (MAIT) cells during alcohol-related liver disease

“…MAIT cells reportedly have profibrogenic function [8], tissue repair [9] and antitumor [10] function. The diagnostic and prognostic value of MAIT cells in Type 1 diabetes [11] and cancer [12] have been reported. MAIT cells are also associated with the progression of HBV infection [13].…”