A modified immune cell infiltration score achieves ideal stratification for CD8+ T cell efficacy and immunotherapy benefit in hepatocellular carcinoma

Abstract

Immunotherapy, which aims to enhance the function of T cells, has emerged as a novel therapeutic approach for hepatocellular carcinoma (HCC). Nevertheless, the clinical utility of using flow cytometry to assess immune cell infiltration (ICI) is hindered by its cumbersome procedures, prompting the need for more accessible methods. Here, we acquired gene expression profiles and survival data of HCC from TCGA and GSE10186 datasets. The patients were categorized into two clusters of ICI, and a set of 11 characteristic genes responsible for the differentiation performance of these ICI clusters were identified. Subsequently, we successfully developed a modified ICI score (mICIS) by utilizing the expression levels of these genes. The efficacy of our mICIS was confirmed via mass cytometry, flow cytometry, and immunohistochemistry. Our research indicated that the favorable overall survival (OS) rate could be attributed to the improved function of anti-tumor leukocytes rather than their infiltration. Furthermore, we observed that the low score group exhibited lower expression levels of T-cell exhaustion-associated genes, which was confirmed in both HCC tissues from patients and mice, which demonstrated that the benefits of the low scores were due to enhanced active/cytotoxic CD8⁺ T cells and reduced exhausted CD8⁺ T cells. Additionally, our mICIS stratified the benefits derived from immunotherapies. Lastly, we observed a misalignment between CD8⁺ T-cell infiltration and function in HCC. In summary, our mICIS demonstrated proficiency in assessing the OS rate of HCC and offering significant stratified data pertaining to distinct responses to immunotherapy.

Keywords: CD8+ T cell; HCC; Immune cell infiltration score; Immunotherapy; Tumor immune microenvironment.