HGH1 and the immune landscape: a novel prognostic marker for immune-desert tumor microenvironment identification and immunotherapy outcome prediction in human cancers

Abstract

ABSTRACT HGH1 homolog, a protein-coding gene, plays a crucial role in human growth and development. However, its role in human cancer remains unclear. For the first time, this study comprehensively evaluated the potential involvement of HGH1 in cancer prognosis and immunological function. To achieve this, data from various databases, including The Cancer Genome Atlas, Genotype Tissue Expression, Cancer Cell Lineage Encyclopedia, Human Protein Atlas, cBioPortal, Tumor Immune Estimation Resource and Immune Cell Abundance Identifier, were collated, as well as from one large clinical study, three immunotherapy cohorts and in vitro experiments. This study aims to elucidate the role of HGH1 expression in cancer prognosis and immune response. Our findings revealed a significant association between increased HGH1 expression and a worse prognosis across various cancer types. Predominantly, copy number variations were identified as the most common genetic mutations. Additionally, HGH1 was observed to not only regulate cell cycle-related functions to promote cell proliferation but also influence autoimmunity-related functions within both the innate and adaptive immune systems, along with other relevant immune-related signaling pathways. Gene set enrichment analysis and gene set variation analysis were used to substantiate these findings. HGH1 overexpression contributed to an immune-deficient (immune-desert) tumor microenvironment, which was characterized by a significant expression of immune-related features such as immune-related gene and pathway expression and the number of immune-infiltrating cells. Furthermore, the correlation between HGH1 expression and tumor mutational burden in four cancers and microsatellite instability in eight cancers was observed. This suggests that HGH1 has potential as an immunotherapeutic target. Immunotherapy data analysis supports this notion, demonstrating that patients with low HGH1 expression treated with immune checkpoint inhibitors exhibit improved survival rates and a higher likelihood of responding to immunotherapy than patients with high HGH1 expression. Collectively, these findings highlight the significant role of HGH1 in human cancers, illuminating its involvement in tumorigenesis and cancer immunity. Elevated HGH1 expression was identified to be indicative of an immune-desert tumor microenvironment. Consequently, the targeting of HGH1, particularly in combination with immune checkpoint inhibitor therapy, holds promise for enhancing therapeutic outcomes in patients with cancer.