Dataset Information

Integrated investigation of the prognostic role of HLA LOH in advanced lung cancer patients with immunotherapy.

ABSTRACT: Although multiple studies have shown that loss of heterozygosity (LOH) at the human leukocyte antigen (HLA) locus is one of the mechanisms of immune escape, the effect of HLA LOH on the immunotherapy response of patients is still unclear. Based on the data of 425 Chinese lung cancer patients, the genomic characteristics with different HLA LOH statuses were analyzed. The driver genes mutation frequency, oncogenic signaling pathways mutation frequency, tumor mutational burden (TMB) and chromosomal instability (CIN) score in the HLA LOH high group was significantly higher than in the HLA LOH negative group. Transcriptome analyses revealed that pre-existing immunologically active tumor microenvironment (TME) was associated with HLA LOH negative patients. Non-small cell lung cancer (NSCLC) patients, especially for lung squamous cell carcinomas (LUSC), with HLA LOH negative have a longer survival period than those with HLA LOH. In addition, the combination of HLA LOH with TMB or programmed cell death-Ligand 1 (PD-L1) expression can further distinguish responders from non-responders. Furthermore, a comprehensive predictive model including HLA LOH status, TMB, PD-L1 expression and CD8⁺ T cells was constructed and exhibited a higher predictive value, which may improve clinical decision-making.

SUBMITTER: Zhang X

PROVIDER: S-EPMC9751360 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Integrated investigation of the prognostic role of HLA LOH in advanced lung cancer patients with immunotherapy.

Zhang Xiaotao X Tang Hongzhen H Luo Haitao H Lu Huiping H Pan Chaohu C Yu Haiming H Zhang Linlin L Guan Yaping Y Yu Lan L Chu Huili H Chen Jun J Wang Jun J

Frontiers in genetics 20221201

Although multiple studies have shown that loss of heterozygosity (LOH) at the human leukocyte antigen (HLA) locus is one of the mechanisms of immune escape, the effect of HLA LOH on the immunotherapy response of patients is still unclear. Based on the data of 425 Chinese lung cancer patients, the genomic characteristics with different HLA LOH statuses were analyzed. The driver genes mutation frequency, oncogenic signaling pathways mutation frequency, tumor mutational burden (TMB) and chromosomal ...[more]

PMID: 36531232

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Project description:Triple-negative breast cancers (TNBCs), especially those non-immune-inflamed tumors, have a poor prognosis and limited therapies. Human leukocyte antigen (HLA)-I not only contributes to antitumor immune response and the phenotype of the tumor microenvironment, but also is a negative predictor of outcomes after immunotherapy. However, the importance of HLA functional status in TNBCs remains poorly understood. Using the largest original multiomics datasets on TNBCs, we systematically characterized the HLA-Ⅰ status of TNBCs from the perspective of HLA-Ⅰ homogeneity and loss of heterozygosity (LOH). The prognostic significance of HLA-I status was measured. To explain the potential mechanism of prognostic value in HLA-Ⅰ status, the mutational signature, copy number alteration, neoantigen and intratumoral heterogeneity were measured. Furthermore, the correlation between HLA-Ⅰ functional status and the tumor immune microenvironment was analyzed. LOH and homogeneity in HLA-I accounted for 18% and 21% of TNBCs, respectively. HLA-I LOH instead of HLA-I homogeneity was an independent prognostic biomarker in TNBCs. In particular, for patients with non-immune-inflamed tumors, HLA-I LOH indicated a worse prognosis than HLA-I non-LOH. Furthermore, integrated genomic and transcriptomic analysis showed that HLA-I LOH was accompanied by upregulated scores of mutational signature 3 and homologous recombination deficiency scores, which implied the failure of DNA double-strand break repair. Moreover, HLA-I LOH had higher mutation and neoantigen loads and more subclones than HLA-I non-LOH. These results indicated that although HLA-I LOH tumors with failure of DNA double-strand break repair were prone to produce neoantigens, their limited capacity for antigen presentation finally contributed to poor immune selection pressure. Our study illustrates the genomic landscape of HLA-I functional status and stresses the prognostic significance of HLA-I LOH in TNBCs. For "cold" tumors in TNBCs, HLA-I LOH indicated a worse prognosis than HLA-I non-LOH.

Project description:BackgroundIt remains controversial whether the platelet to lymphocyte ratio (PLR) serves as a potential indicator for the efficacy of immunotherapy in advanced lung cancer. This meta-analysis aimed to address this concern.MethodsUp to March 2022, we searched PubMed, Embase, Web of Science and the Cochrane Library to retrieve potentially eligible articles. Combined hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated to assess the relationship between PLR and progression-free survival (PFS) as well as overall survival (OS), while the combined odds ratios (ORs) and 95% CIs were estimated to evaluate the relationship between PLR and the objective response rate (ORR) as well as the disease control rate (DCR). Subgroup analyses were further performed to detect the source of heterogeneity and potential predictive value of PLR in different groups in terms of OS and PFS.ResultsA total of 21 included studies involving 2312 patients with advanced lung cancer receiving immunotherapy were included. The combined results suggested that elevated PLR was associated with poorer OS (HR=2.24; 95% CI: 1.87-2.68; I² =44%; P=0.01) and PFS (HR=1.66; 95% CI: 1.36-2.04; I² =64%; P<0.01). Furthermore, elevated PLR showed a lower ORR (OR= 0.61; 95% CI: 0.43-0.87, I²=20%; P=0.29) and DCR (OR= 0.44; 95% CI: 0.27-0.72, I²=61%; P=0.02). In subgroup analyses, pretreatment PLR was significantly associated with adverse OS and PFS. The same results were observed in different PLRs in terms of cutoff value (>200 vs. ≤200). Furthermore, high PLR was significantly associated with poor OS and PFS in advanced non-small cell lung cancer (NSCLC); however, PLR was not associated with OS and PFS in advanced small cell lung cancer (SCLC). In addition, PLR predicted poor OS irrespective of regions and types of immune checkpoint inhibitors (ICIs).ConclusionOn the whole, patients with low PLR had better OS and PFS, as well as higher ORR and DCR when receiving immunotherapy in advanced lung cancer especially for advanced NSCLC. And further investigations are warranted to confirm the prognostic value of PLR in advanced SCLC.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022315976.

Project description:BACKGROUND: Cancer and other disorders are due to genomic lesions. SNP-microarrays are able to measure simultaneously both genotype and copy number (CN) at several Single Nucleotide Polymorphisms (SNPs) along the genome. CN is defined as the number of DNA copies, and the normal is two, since we have two copies of each chromosome. The genotype of a SNP is the status given by the nucleotides (alleles) which are present on the two copies of DNA. It is defined homozygous or heterozygous if the two alleles are the same or if they differ, respectively. Loss of heterozygosity (LOH) is the loss of the heterozygous status due to genomic events. Combining CN and LOH data, it is possible to better identify different types of genomic aberrations. For example, a long sequence of homozygous SNPs might be caused by either the physical loss of one copy or a uniparental disomy event (UPD), i.e. each SNP has two identical nucleotides both derived from only one parent. In this situation, the knowledge of the CN can help in distinguishing between these two events. RESULTS: To better identify genomic aberrations, we propose a method (called gBPCR) which infers the type of aberration occurred, taking into account all the possible influence in the microarray detection of the homozygosity status of the SNPs, resulting from an altered CN level. Namely, we model the distributions of the detected genotype, given a specific genomic alteration and we estimate the parameters involved on public reference datasets. The estimation is performed similarly to the modified Bayesian Piecewise Constant Regression, but with improved estimators for the detection of the breakpoints.Using artificial and real data, we evaluate the quality of the estimation of gBPCR and we also show that it outperforms other well-known methods for LOH estimation. CONCLUSIONS: We propose a method (gBPCR) for the estimation of both LOH and CN aberrations, improving their estimation by integrating both types of data and accounting for their relationships. Moreover, gBPCR performed very well in comparison with other methods for LOH estimation and the estimated CN lesions on real data have been validated with another technique.

Project description:BackgroundImmune checkpoint inhibitors (ICIs) represent a great breakthrough in the treatment of advanced non-small cell lung cancer (aNSCLC). However, whether immunotherapy beyond progression (IBP) is effective for aNSCLC has yet to be established. Therefore, a retrospective clinical study was conducted to investigate the efficacy of IBP in patients with aNSCLC under real-world conditions.MethodsA total of 125 Chinese patients with aNSCLC who experienced progressive disease (PD) after receiving monotherapy or combination therapy (combined with chemotherapy or/and antiangiogenic therapy) with programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors between January 2015 and March 2019 were enrolled. Patients who were treated with ICIs for more than 6 weeks after PD were defined as IBP (n=39), while those who received ICI treatment for less than 6 weeks or discontinued it due to PD were defined as non-IBP (n=86). Patient clinical characteristics were evaluated. An optimization-based method was applied to balance the clinical baseline characteristics between the two groups.ResultsIn total population, the IBP group had longer overall survival (median OS, 26.6 vs. 9.5 months; HR, 0.40; 95% CI: 0.23-0.69; P<0.001) and progression-free survival (median PFS, 8.9 vs. 4.1 months; HR, 0.41; 95% CI: 0.26-0.65; P<0.001), compared with the non-IBP group. Despite no significant difference in objective response rate (ORR, 15.4% vs. 11.6%, P=0.560), disease control rate (DCR) was significantly higher in the IBP group (89.7% vs. 61.6%, P<0.001). After balancing baseline covariates, the IBP group also had longer OS (median: 26.6 vs. 10.7 months; HR, 0.40; 95% CI: 0.19-0.84; P=0.015) and PFS (median: 9.7 vs. 4.3 months; HR, 0.28; 95% CI: 0.15-0.51; P<0.001), with a benefit in either of patients previously treated with ICI monotherapy or in combination therapy and with non-response to the previously ICI.ConclusionsIBP is associated with longer OS and PFS in patients with aNSCLC. Our findings may suggest new therapeutic options for patients with aNSCLC who experienced disease progression after initial immunotherapy.

Dataset Information

Integrated investigation of the prognostic role of HLA LOH in advanced lung cancer patients with immunotherapy.

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Integrated investigation of the prognostic role of HLA LOH in advanced lung cancer patients with immunotherapy.

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