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Association between HLA-DRB1*04:05 and the efficacy of immune checkpoint inhibitors for patients with advanced cancer
Mayu Watanabe1,2, Jun Eguchi2, Atsushi Takamoto3
1Department of Diabetology and Endocrinology, NHO Okayama Medical Center, Okayama, Japan.
Introduction:
Tumor cells use immune checkpoint proteins such as programmed cell death 1 to escape immunological defenses. Immune checkpoint inhibitors (ICIs) that target these proteins have been used to treat several malignancies. ICI-induced diabetes is a rare but life-threatening adverse event. Our previous study evaluated pancreatic β-cell activity using the homeostasis model assessment of β-cell (HOMA-β) function before ICI treatment and demonstrated its association with treatment outcomes. In addition, DRB1*04:05 and DRB1*09:01 reportedly increase the risk of type 1 diabetes in Japanese patients, whereas DRB1*15:01 protected against type 1 diabetes. However, the association between human leukocyte antigen (HLA) class II alleles and treatment outcomes of ICI therapy remains unclear.
Methods:
We included 96 patients who were diagnosed with advanced cancer. The HLA genotypes that cause type 1 diabetes in patients with ICI-treated cancers were evaluated to determine their association with the cancer prognosis.
Results:
The median progression-free survival (PFS) in the DRB1*04:05-positive group (2 months, 95% confidence interval [CI]: 1.214-2.786; 31 events; 1 censored event) was significantly shorter than that in the DRB1*04:05-negative group (3 months; 95% CI: 1.933-4.067; 56 events; 8 censored events) (log rank p=0.045). Additionally, a multivariable Cox proportional hazards regression revealed that DRB1*04:05 was independently associated with shorter PFS for patients treated with ICIs.
Conclusions:
HLA class II alleles were associated with shorter PFS in patients treated with ICIs. In particular, DRB1*04:05 positivity was associated with worse survival outcomes, suggesting a potential immunogenetic contribution to treatment outcomes.
Insights
Human leukocyte antigen (HLA) class II alleles impact cancer treatment outcomes with immune checkpoint inhibitors (ICIs). DRB1*04:05 positivity is linked to shorter progression-free survival in patients receiving ICIs.
Area of Science:
- Immunogenetics
- Oncology
- Endocrinology
Background:
- Immune checkpoint inhibitors (ICIs) treat malignancies by targeting immune checkpoints like programmed cell death 1.
- ICI-induced diabetes is a rare but severe adverse event.
- Previous research linked pancreatic beta-cell function (HOMA-β) to ICI treatment outcomes and specific human leukocyte antigen (HLA) alleles to type 1 diabetes risk.
Purpose of the Study:
- To investigate the association between human leukocyte antigen (HLA) class II alleles and treatment outcomes in advanced cancer patients receiving ICIs.
- To determine if specific HLA genotypes influence cancer prognosis in the context of ICI therapy.
Main Methods:
- Retrospective analysis of 96 advanced cancer patients treated with ICIs.
- Evaluation of HLA genotypes, particularly those associated with type 1 diabetes.
- Correlation of HLA alleles with cancer prognosis, including progression-free survival (PFS).
Main Results:
- A significant association was found between HLA class II alleles and PFS in patients treated with ICIs.
- Patients positive for the DRB1*04:05 allele exhibited significantly shorter median progression-free survival (2 months) compared to those negative for it (3 months).
- Multivariable Cox regression analysis confirmed DRB1*04:05 as an independent predictor of shorter PFS in the ICI-treated cohort.
Conclusions:
- Specific HLA class II alleles are associated with treatment outcomes in patients receiving ICIs.
- The presence of the DRB1*04:05 allele is linked to worse survival outcomes, suggesting an immunogenetic factor influencing ICI efficacy.
- These findings highlight the potential role of immunogenetics in predicting and understanding responses to ICI therapy.
