Predictive factors of response to immunotherapy—a review from the Spanish Melanoma Group (GEM)

Espinosa, Enrique; Márquez-Rodas, Iván; Soria, Ainara; Berrocal, A.; Manzano, José Luís; González‐Cao, María; Martín‐Algarra, Salvador

doi:10.21037/atm.2017.08.10

Cited by 32 publications

(24 citation statements)

References 43 publications

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“…Many studies have shown that the infiltration of CD8 + cytotoxic T cells plays key roles in the cancer-initiating cell (CIC) response (20), but the roles and clinical impact of FOXp3 + regulatory T cells on the CIC response are not fully understood (21). A previous report has shown that PD-L1 expression in SM (22,23), and all types of melanoma (24) is associated with CD8 + lymphocytes, consistent with our findings.…”

Section: Discussionsupporting

confidence: 90%

PD‑L1 expression in malignant melanomas of the skin and gastrointestinal tract

et al. 2020

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Gastrointestinal melanoma (GM) is a rare but aggressive type of malignant melanoma arising in the gastrointestinal tract. An anti-programmed cell death protein 1 (PD-1) antibody markedly improves prognosis in patients with melanoma. However, little is known regarding the expression of immune-oncology biomarkers in GM compared with skin melanoma (SM), especially in the Asian population. the present study examined clinicopathological characteristics, PD-L1 and HLA expression, and immune-oncology marker expression in 10 cases of GM and 31 cases of SM. Patients with GM exhibited significantly higher incidences of lymph node and distant metastases than patients with SM (P=0.0448 and P=0.0247, respectively). The infiltration of CD8 + lymphocytes was significantly higher in GM than in SM (P=0.0231). The infiltration of PD-1 + lymphocytes was higher in GM than in SM, but the difference was not significant (P=0.0975). PD-L1-positive melanoma exhibited a higher proportion of BRAF V600E-positive melanoma than PD-L1-negative melanoma (P=0.0317; 39.4 and 0%, respectively). PD-L1-positive melanoma exhibited significantly higher rates of CD8 + and FOXp3 + lymphocyte infiltration than PD-L1-negative melanoma (P=0.0221 and P=0.0463, respectively). By contrast, PD-1 + lymphocytes did not differ between PD-L1-positive and-negative cases. Furthermore, HLA-positive melanoma exhibited higher proportions of PD-1 (P=0.0101; 53.7 and 15.4%) and CD8 than HLA-negative melanoma (P= 0.0818; 66.7 and 38.2%). These results provided useful information regarding tumor immunity in GM and SM and may contribute to the development of treatment strategies for GM.

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Section: Discussionsupporting

confidence: 90%

PD‑L1 expression in malignant melanomas of the skin and gastrointestinal tract

et al. 2020

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“…Peripheral blood markers were examined to better characterize the cases in reference to the clinical benefits in immunotherapy. An elevated lactate dehydrogenase (LDH) level was reported to be indicator of tumor burden that is typically associated with lower response rates to immunotherapy, while an elevated platelet-lymphocyte ratio (PLR) was also associated with lower response rates in patients treated with immunotherapy [ 12 ]. The pre-surgery blood exam data were analyzed, which revealed that serum LDH levels were significantly higher in thymomas with mutant GTF2I than those with wildtype GTF2I (thymomas with mutant GTF2I , 224.3 ± 13.3; thymomas with wildtype GTF2I , 183.7 ± 12.1; p < 0.05).…”

Section: Resultsmentioning

confidence: 99%

Primary Driver Mutations in GTF2I Specific to the Development of Thymomas

Higuchi

Goto

Hirotsu

et al. 2020

Cancers

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Thymomas are rare mediastinal tumors that are difficult to treat and pose a major public health concern. Identifying mutations in target genes is vital for the development of novel therapeutic strategies. Type A thymomas possess a missense mutation in GTF2I (chromosome 7 c.74146970T>A) with high frequency. However, the molecular pathways underlying the tumorigenesis of other thymomas remain to be elucidated. We aimed to detect this missense mutation in GTF2I in other thymoma subtypes (types B). This study involved 22 patients who underwent surgery for thymomas between January 2014 and August 2019. We isolated tumor cells from formalin-fixed paraffin-embedded tissues from the primary lesions using laser-capture microdissection. Subsequently, we performed targeted sequencing to detect mutant GTF2I coupled with molecular barcoding. We used PyClone analysis to determine the fraction of tumor cells harboring mutant GTF2I. We detected the missense mutation (chromosome 7 c.74146970T>A) in GTF2I in 14 thymomas among the 22 samples (64%). This mutation was harbored in many type B thymomas as well as type A and AB thymomas. The allele fraction for the tumors containing the mutations was variable, primarily owing to the coexistence of normal lymphocytes in the tumors, especially in type B thymomas. PyClone analysis revealed a high cellular prevalence of mutant GTF2I in tumor cells. Mutant GTF2I was not detected in other carcinomas (lung, gastric, colorectal, or hepatocellular carcinoma) or lymphomas. In conclusion, the majority of thymomas harbor mutations in GTF2I that can be potentially used as a novel therapeutic target in patients with thymomas.

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“…In line with these results, we found PD-L2 DNA methylation and mRNA expression to be correlated with known prognostic factors, such as tumor-infiltrating lymphocytes and an IFN-γ signature. Tumor-infiltrating lymphocytes are known to be associated with favorable prognosis in primary and advanced melanoma [42,43]. An IFN-γ signature has been shown to be associated with response to immune checkpoint inhibitors [44,45].…”

Section: Discussionmentioning

confidence: 99%

Prognostic and predictive value of PD-L2 DNA methylation and mRNA expression in melanoma

et al. 2020

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Background: PD-L1 (programmed cell death 1 ligand 1) expression in melanoma has been associated with a better response to anti-PD-1 (programmed cell death 1) therapy. However, patients with PD-L1-negative melanomas can respond to anti-PD-1 blockade, suggesting that the other PD-1 ligand, PD-L2 (programmed cell death 1 ligand 2), might also be relevant for efficacy of PD-1 inhibition. We investigated PD-L2 expression and methylation as a prognostic and predictive biomarker in melanoma. Methods: DNA methylation at five CpG loci and gene expression of PD-L2 were evaluated with regard to survival in 470 melanomas from The Cancer Genome Atlas. PD-L2 promoter methylation in correlation with PD-L2 mRNA and protein expression was analyzed in human melanoma cell lines. Prognostic and predictive value of PD-L2 methylation was validated using quantitative methylation-specific PCR in a multicenter cohort of 129 melanoma patients receiving anti-PD-1 therapy. mRNA sequencing data of 121 melanoma patients receiving anti-PD-1 therapy provided by Liu et al. were analyzed for PD-L2 mRNA expression. Results: We found significant correlations between PD-L2 methylation and mRNA expression levels in melanoma tissues and cell lines. Interferon-γ inducible PD-L2 protein expression correlated with PD-L2 promoter methylation in melanoma cells. PD-L2 DNA promoter hypomethylation and high mRNA expression were found to be strong predictors of prolonged overall survival. In pre-treatment melanoma samples from patients receiving anti-PD-1 therapy, low PD-L2 DNA methylation and high PD-L2 mRNA expression predicted longer progression-free survival. Conclusion: PD-L2 expression seems to be regulated via DNA promoter methylation. PD-L2 DNA methylation and mRNA expression may predict progression-free survival in melanoma patients receiving anti-PD-1 immunotherapy. Assessment of PD-L2 should be included in further clinical trials with anti-PD-1 antibodies.

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Predictive factors of response to immunotherapy—a review from the Spanish Melanoma Group (GEM)

Cited by 32 publications

References 43 publications

PD‑L1 expression in malignant melanomas of the skin and gastrointestinal tract

PD‑L1 expression in malignant melanomas of the skin and gastrointestinal tract

Primary Driver Mutations in GTF2I Specific to the Development of Thymomas

Prognostic and predictive value of PD-L2 DNA methylation and mRNA expression in melanoma

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