Germline HLA-B evolutionary divergence influences the efficacy of immune checkpoint blockade therapy in gastrointestinal cancer

Lü, Zhihao; Chen, Huan; Ji, Xi; Wang, Yujiao; Wu, Lijia; Sun, Huaibo; Li, Shuang; Gong, Jifang; Li, Jian; Zou, Jianling; Yang, Keyan; Hu, Ying; Mao, Beibei; Zhang, Lei; Zhang, Xiaotian; Peng, Zhi; Lu, Ming; Wang, Zhenghang; Zhang, Henghui; Shen, Lin

doi:10.1186/s13073-021-00997-6

Cited by 14 publications

(10 citation statements)

References 72 publications

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“…Future evaluations of the impact of HLA-I diversity should be refined by taking these factors into consideration. Notably, in the analyses of outcomes in patients with melanoma and non-small cell lung cancer treated with immune checkpoint inhibitors, higher HED was significantly correlated with better survival, whereas higher Pr yielded worse prognosis, suggesting the influence of HLA-I variations on the response to immunotherapy [ 7 , 9 , 19 ]. The role of HLA-I diversity in sensitivity to immunotherapy in breast cancer needs further exploration in prospective clinical trials.…”

Section: Discussionmentioning

confidence: 99%

The HLA-I landscape confers prognosis and antitumor immunity in breast cancer

Ding,

Xiao,

Chen

et al. 2024

Briefings in Bioinformatics

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Breast cancer is a highly heterogeneous disease with varied subtypes, prognoses and therapeutic responsiveness. Human leukocyte antigen class I (HLA-I) shapes the immunity and thereby influences the outcome of breast cancer. However, the implications of HLA-I variations in breast cancer remain poorly understood. In this study, we established a multiomics cohort of 1156 Chinese breast cancer patients for HLA-I investigation. We calculated four important HLA-I indicators in each individual, including HLA-I expression level, somatic HLA-I loss of heterozygosity (LOH), HLA-I evolutionary divergence (HED) and peptide-binding promiscuity (Pr). Then, we evaluated their distribution and prognostic significance in breast cancer subtypes. We found that the four breast cancer subtypes had distinct features of HLA-I indicators. Increased expression of HLA-I and LOH were enriched in triple-negative breast cancer (TNBC), while Pr was relatively higher in hot tumors within TNBCs. In particular, a higher Pr indicated a better prognosis in TNBCs by regulating the infiltration of immune cells and the expression of immune molecules. Using the matched genomic and transcriptomic data, we found that mismatch repair deficiency-related mutational signature and pathways were enriched in low-Pr TNBCs, suggesting that targeting mismatch repair deficiency for synthetic lethality might be promising therapy for these patients. In conclusion, we presented an overview of HLA-I indicators in breast cancer and provided hints for precision treatment for low-Pr TNBCs.

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Section: Discussionmentioning

confidence: 99%

The HLA-I landscape confers prognosis and antitumor immunity in breast cancer

Ding,

Xiao,

Chen

et al. 2024

Briefings in Bioinformatics

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“…Since heterozygosity at classical HLA-I genes or high HED levels of HLA-B alleles had been found to be associated with improved survival in cancer patients treated with ICIs ( 45 , 46 ), we assumed that individuals who are heterozygous for HLA or with high HED levels also have a higher incidence of irAEs. However, our outcomes pointed out that the correlation between heterozygosity and HLA certain types might be weak, regardless of treatment strategies and the irAEs subtype.…”

Section: Discussionmentioning

confidence: 99%

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

Jiang

Yu²,

Zhang³

et al. 2022

Front. Immunol.

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BackgroundIn recent years, significant progress has been made in immune checkpoint inhibitors (ICIs). However, accompanied by remarkable efficacy, a growing number of immune-related adverse events (irAEs) also arose. The mechanism of irAEs remains unclear. Previous studies indicated a positive association between specific human leukocyte antigen (HLA) variants and irAEs. Therefore, we planned and initiated a large cohort study aiming to uncover the relationship between irAEs and divergent HLA types.MethodsWe screened all patients who have been treated in the clinical research ward, Cancer Hospital of the Chinese Academy of Medical Sciences. All participants were diagnosed with malignant tumors with complete AE follow-up data in the original electronic medical records. Sequencing libraries were generated using a customized panel, and four-digit formatted HLA alleles were extracted for further analysis. Association analysis was performed between HLA variants and different irAEs. We introduced two external reference groups and a non-irAE control group within the study cohort to control the type I error. We also explored the relationship between the zygosity of HLA genes, the evolutionary divergence of HLA class I genotype (HED), and irAEs.Results530 participants received at least two doses of ICIs. The median follow-up time was 10.3 months. 97% of patients received anti-PD-1/PD-L1 treatment. The occurrence of overall irAEs showed no significant difference between the HLA homozygous group and the HLA 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 and detected a 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), 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).ConclusionsIrAEs in specific organs and tissues may be associated with certain HLA types, while HLA heterogeneity has 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.

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“…Therefore, the mechanism for the ICIs response is to activate the immune system, which depends on the antigenicity of the tumor and the efficiency of antigen presentation. Theoretically, greater HLA diversity leads to a greater variety of tumor neoantigens being presented, which could increase the efficacy of treatment with ICIs ( 24 ). HLA-B44 is a supertype of HLA-I, which could cross-present new antigens presented by other subtypes of HLA, thus increasing the diversity of HLAs and activating T cells to kill tumor cells ( 24 , 25 ).…”

Section: Discussionmentioning

confidence: 99%

“…Theoretically, greater HLA diversity leads to a greater variety of tumor neoantigens being presented, which could increase the efficacy of treatment with ICIs ( 24 ). HLA-B44 is a supertype of HLA-I, which could cross-present new antigens presented by other subtypes of HLA, thus increasing the diversity of HLAs and activating T cells to kill tumor cells ( 24 , 25 ). Recently, over 50 clinical trials for ovarian cancer were related to immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

A durable response to programmed cell death 1 blockade in a multidrug-resistant recurrent ovarian cancer patient with HLA-B44 supertype: A case report

Luo

Sun²,

Li³

et al. 2022

Front. Immunol.

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Relapsed/refractory ovarian cancer, especially platinum resistance recurrence, remains a major therapeutic challenge. Here, we present the case of a patient with recurrent ovarian clear cell carcinoma (OCCC) who failed to respond to multiline chemotherapy and target therapy but achieved an immune complete response (iCR) with programmed cell death 1 (PD-1) inhibitor treatment. The overall survival (OS) was 59 months, and the recurrence-free survival (RFS) was 34 months after immunotherapy, which was counting. Meantime, molecular testing results revealed that traditional biomarkers for immunotherapy, including PD-L1 expression, microsatellite instability (MSI), and tumor mutational burden (TMB), were negative. HLA-B44 (B*18:01) supertype was confirmed by sequence-based HLA typing. This case raises the possibility that ovarian cancer patients with multidrug resistance may still benefit from PD-1 inhibitor therapy, even if PD-L1 pathology is negative.

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Germline HLA-B evolutionary divergence influences the efficacy of immune checkpoint blockade therapy in gastrointestinal cancer

Cited by 14 publications

References 72 publications

The HLA-I landscape confers prognosis and antitumor immunity in breast cancer

The HLA-I landscape confers prognosis and antitumor immunity in breast cancer

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

A durable response to programmed cell death 1 blockade in a multidrug-resistant recurrent ovarian cancer patient with HLA-B44 supertype: A case report

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