Role of Human Leukocyte Antigen System as A Predictive Biomarker for Checkpoint-Based Immunotherapy in Cancer Patients

Abstract

Recent advances in cancer immunotherapy have clearly shown that checkpoint-based immunotherapy is effective in a small subgroup of cancer patients. However, no effective predictive biomarker has been identified so far. The major histocompatibility complex, better known in humans as human leukocyte antigen (HLA), is a very polymorphic gene complex consisting of more than 200 genes. It has a crucial role in activating an appropriate host immune response against pathogens and tumor cells by discriminating self and non-self peptides. Several lines of evidence have shown that down-regulation of expression of HLA class I antigen derived peptide complexes by cancer cells is a mechanism of tumor immune escape and is often associated to poor prognosis in cancer patients. In addition, it has also been shown that HLA class I and II antigen expression, as well as defects in the antigen processing machinery complex, may predict tumor responses in cancer immunotherapy. Nevertheless, the role of HLA in predicting tumor responses to checkpoint-based immunotherapy is still debated. In this review, firstly, we will describe the structure and function of the HLA system. Secondly, we will summarize the HLA defects and their clinical significance in cancer patients. Thirdly, we will review the potential role of the HLA as a predictive biomarker for checkpoint-based immunotherapy in cancer patients. Lastly, we will discuss the potential strategies that may restore HLA function to implement novel therapeutic strategies in cancer patients.

Development of an Immune-Related Gene Signature for Prognosis in Melanoma

“…Polymorphisms of human leukocyte antigen (HLA) genes are thought to be associated with the susceptibility to a variety of malignancies and involved in the progress of carcinogenesis, tumor proliferation and immune escape ( 30 ). HLA-DQB1 is more extensively studied in gastric cancer and cervical cancer ( 31 , 32 ).…”

Pharmacogenomic Biomarkers in US FDA-Approved Drug Labels (2000–2020)

“…Mismatch repair deficiency/microsatellite instability is a predictor of anti-PD-1/anti-PD-L1 treatment efficacy in solid tumors such as colorectal cancer [33,34]. Human leukocyte antigen (HLA) is another promising biomarker as it plays a major role in discerning foreign pathogens or tumor cells as part of the anti-tumor immune response [35]. Research suggests that a patient's HLA type might be indicative of response to immunotherapy and can be utilized in personalized cancer vaccine development and immunotherapy biomarker discovery [36].…”

Biology of NSCLC: Interplay between Cancer Cells, Radiation and Tumor Immune Microenvironment

“…Table 1 represents latest evidence on tumor-related immunosuppressive effects . Tumor cells escape immune surveillance by downregulation of HLA and co-stimulatory molecules, or by production of immunosuppressive factors and upregulation of immune cell apoptosis inducing molecules [23][24][25][26]. As a consequence, the immune system will "ignore and tolerate" tumor cell proliferation and progression.…”

“…Table 1 represents latest evidence on tumor-related immunosuppressive effects [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ]. Tumor cells escape immune surveillance by downregulation of HLA and co-stimulatory molecules, or by production of immunosuppressive factors and upregulation of immune cell apoptosis inducing molecules [ 23 , 24 , 25 , 26 ]. As a consequence, the immune system will “ignore and tolerate” tumor cell proliferation and progression.…”