Effect of HLA Typing on Human Intestinal Cancer Research

In recent years, significant progress has been made in the research on the pathogenesis of cancer. Researchers have gradually realized that human leukocyte antigen (Human Leucocyte Antigen, HLA) alleles are directly involved in the pathogenesis. HLA is human leukocyte antigen, also known as the major histocompatibility complex (MHC), which coded on the short arm of chromosome 6. HLA genes can be divided into three categories according to their structure and function. It has been confirmed that there are genes controlling the immune response in the HLA complex and that HLA participates in binding the interaction between immune cells, which means that HLA involves various levels and aspects of life activities, especially closely related to disease susceptibility and adverse drug reactions. It is noteworthy that HLA plays an important role in the regulation of the interaction between the body and drugs, and HLA research has developed into an independent discipline branch.

The distribution of HLA gene

HLA genotyping for personalized drug selection for intestinal cancer

Anti–tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. However, repeated administration can induce the formation of anti-drug antibodies (immunogenicity), leading to treatment failure. The ability to identify patients at increased risk of

immunogenicity may influence the choice of anti-TNF treatment and the use of preventative strategies, including combination therapy with immunomodulators. Researchers conducted a genome-wide association study on 1240 patients with Crohn's disease who were initially treated with infliximab or adalimumab, and found that the risk of anti-drug antibody production in patients with HLA-DQA1 * 05 was almost doubled regardless of whether they were combined with immunosuppressants. Collectively, in order to minimize the risk of immunogenicity, HLA-DQA1 * 05 gene detection before treatment may be helpful for personalized selection of anti-TNF drugs and immunosuppressant combination therapy.

A regional plot of the association results with the major histocompatibility complex (MHC) region on chromosome 6.

HLA-DQA1 * 05 has a consistent effect on the immunogenicity of different patient subgroups

Effect of HLA-B gene on the efficacy of immunotherapy for gastrointestinal tumors

The human leukocyte antigen class I (HLA-I) genotype has been linked with differential immune responses to infectious disease and cancer. A recent study retrospectively analyzed the genomic profiling data from 84 metastatic GI cancer patients treated with immune checkpoint blockade (ICB) recruited from Peking University Cancer Hospital (PUCH). The peripheral blood mononuclear cells (PBMC) of all patients were analyzed by whole exon sequencing (WES) to evaluate the heterozygosity of HLA - Ⅰ molecules (HLA-A, HLA-B, HLA-C) and the evolution difference between HLA - Ⅰ alleles (HED). Tumor tissues from 76 patients were subjected to WES analysis and immune oncology-related RNA profiling. The data showed that the high level of HLA-B HED shows immunoinflammatory phenotype, which may be related to the improvement of immunotherapy efficacy in patients with gastrointestinal tumors. To sum up, the results of this study reveal how the sequence evolution difference between HLA-B alleles affects the response of gastrointestinal cancer patients to immune checkpoint inhibitors, and support its combination with TMB as a potential biomarker for patient stratification, to help accurately screen the gastrointestinal cancer patients who can benefit from the treatment of immune checkpoint inhibitors.

With the rapid development of life science, people's understanding and requirements for clinical medication have undergone major changes. In-depth study of drug-related HLA gene can help to reverse speculate the possible sensitized drugs, so as to avoid clinical problems such as adverse drug reactions. In the future, it is critical for health care professionals to understand what HLA information (antigen typing, allele typing, or antibody testing) is needed for patient care and what impacts or risks are associated with that HLA type for drug research of intestinal cancer.

References:

1. Carey, B Sean et al. "Factors affecting HLA expression: A review." International journal of immunogenetics vol. 46,5 (2019): 307-320.
2. Fung, Mark K, and Kaaron Benson. "Using HLA typing to support patients with cancer." Cancer control: journal of the Moffitt Cancer Center vol. 22,1 (2015): 79-86.
3. Sullivan, A et al. "Implications of HLA-allele associations for the study of type IV drug hypersensitivity reactions." Expert opinion on drug metabolism & toxicology vol. 14,3 (2018): 261-274.
4. Chowell, Diego et al. "Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy." Nature medicine vol. 25,11 (2019): 1715-1720.
5. Sazonovs, Aleksejs et al. "HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn's Disease." Gastroenterology vol. 158,1 (2020): 189-199.
6. Lu, Zhihao et al. "Germline HLA-B evolutionary divergence influences the efficacy of immune checkpoint blockade therapy in gastrointestinal cancer." Genome medicine vol. 13,1 175. 3 Nov. 2021, doi:10.1186/s13073-021-00997-6