Association between germ-line HLA and immune-related adverse events.

Abstract

2658 Background: In recent years, great progress has been made in immune checkpoint inhibitors (ICIs), opening a new chapter for cancer treatment. However, accompanied by remarkable efficacy, immune-related adverse events (irAEs) also arose. Though some pilot studies have explored the possible factors that may influence the development of irAEs, the mechanism of irAEs remains unclear. Previous studies indicated a positive association between certain HLA types and irAEs. To uncover the relationship between irAEs and divergent HLA types, we initiated a large cohort study. Methods: We screened 626 patients who have been treated in the clinical research ward, Cancer Hospital of Chinese Academy of Medical Sciences. All participants included should be diagnosed with malignant tumors and have received at least 2 cycles of ICIs with complete security follow-up data in the original electronic medical records. The blood samples were collected before the first cycle of treatment. Sequencing libraries were generated using a customized panel. Six digit formatted HLA alleles were extracted from HLA-HD (v1.4.0) results for further analysis. Fisher-exact test was used to perform association analysis between HLA and different irAEs. To control the type I error, we introduce two external reference groups as well as the non-irAE control group. In addition, false discovery rate (FDR) correction was performed with the resulting p-values when comparing the HLA allele frequency between patients with irAEs and the MHC-han Chinese reference cohort. We also explored the relationship between zygosity of HLA genes, evolutionary divergence of HLA class I genotype (HED) and irAEs. Results: Of the 626 participants, 530 received at least 2 doses of ICIs. The median follow-up time was 10.3 months. 97% patients received anti-PD-1/PD-L1 treatment. Of all participants, 78% reported irAEs of any grade, with 10.2% reporting grade 3 and above irAEs. The occurrence of overall irAEs showed no significant difference between homozygous group and heterozygous group. We did not find any significant association between irAEs and HED. We found that some HLA types are associated with irAEs of different organs, including the significant association between HLA-DRB3*01:01 and thrombocytopenia (OR 3.48 (1.19,9.42), p = 0.011), HLA-DPB1*04:02 and hypokalemia/ hyponatremia (OR 3.44 (1.24,9.1), p = 0.009), leukopenia (OR 2.1 (0.92,4.8), p = 0.037) as well as anemia (OR 2.33 (1.0,5.41), p = 0.026), HLA-A*26:01 and bilirubin elevation (OR 2.67 (0.92,8.31), p = 0.037). Conclusions: IrAEs in specific organs and tissues may be associated with certain HLA types, while HLA heterogeneity have no significant influence on the happening of irAEs. More research is needed to explore the role of germline genetic changes in the risk assessment of irAEs, and potential therapies targeting irAE-inducing HLA types without influencing the anticancer effect may be considered to benefit the patients.