Targeted literature review on use of tumor mutational burden status and programmed cell death ligand 1 expression to predict outcomes of checkpoint inhibitor treatment

Krieger, Tina; Pearson, Isobel; Bell, Judith; Doherty, Jim; Robbins, Paul B.

doi:10.1186/s13000-020-0927-9

Cited by 47 publications

(42 citation statements)

References 55 publications

(69 reference statements)

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“…We also examined the associations between PD-1/CTLA4 levels and the expression of TIL markers ( 25 – 27 ). An expression heatmap was generated for gene pairs in specific cancer types and correlations were analyzed with Spearman's rank correlation test.…”

Section: Methodsmentioning

confidence: 99%

Clinical Implications of Aberrant PD-1 and CTLA4 Expression for Cancer Immunity and Prognosis: A Pan-Cancer Study

et al. 2020

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Combination therapy with inhibitors of cytotoxic T lymphocyte-associated protein (CTLA)4 and programmed death (PD)-1 has demonstrated efficacy in cancer patients. However, there is little information on CTLA4 and PD-1 expression levels and their clinical significance across diverse cancers. In this study, we addressed this question by analyzing PD-1 and CTLA4 levels in 33 different types of cancer along with their prognostic significance using The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia datasets. Liver hepatocellular carcinoma (LIHC) patients receiving cytokine-induced killer cell (CIK) immunotherapy at Sun Yat-sen University cancer center were enrolled for survival analysis. The correlation between PD-1/CTLA4 expression and cancer immunity was also analyzed. The results showed that PD-1 and CTLA4 transcript levels varied across cancer cell lines, with aberrant expression detected in certain cancer types; Kaplan–Meier analysis with the Cox proportional hazards model showed that this was closely related to overall survival in breast invasive carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, acute myeloid leukemialymphoma, uterine corpus endometrial carcinoma, and uveal melanoma in TCGA. High serum PD-1 and CTLA4 levels predicted better survival in LIHC patients receiving CIK therapy. PD-1 and CTLA4 levels were found to be significantly correlated with the degree of tumor cell infiltration using Tumor Immune Estimation Resource, Estimating Relative Subsets of RNA Transcripts, and Estimation of Stromal and immune Cells in Malignant Tumor Tissues Using Expression Data as well as with tumor-infiltrating lymphocyte marker expression; they were also related to tumor mutation burden, microsatellite instability, mismatch repair, and the expression of DNA methyltransferases in some cancer types. Gene set enrichment analysis of 33 cancer types provided further evidence for associations between PD-1/CTLA4 levels and cancer development and immunocyte infiltration. Thus, PD-1 and CTLA4 play important roles in tumorigenesis and tumor immunity and can serve as prognostic biomarkers in different cancer types.

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Section: Methodsmentioning

confidence: 99%

Clinical Implications of Aberrant PD-1 and CTLA4 Expression for Cancer Immunity and Prognosis: A Pan-Cancer Study

et al. 2020

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“…The Tumor Mutational Burden (TMB) is usually measured by the number of somatic mutations that occur within an average of 1 Mb in the coding region (exon region) of the tumor cell genome (non-synonymous mutations) (Krieger et al, 2020). The total number of synonymous mutations indicate that the mutation pattern includes single nucleotide mutation (SNV) and small fragment insertion/deletion (Indel) and other forms of mutation.…”

Section: Association Between Ace2 and Immune Neoantigen Tmb Microsamentioning

confidence: 99%

Systematic Analysis of Coronavirus Disease 2019 (COVID-19) Receptor ACE2 in Malignant Tumors: Pan-Cancer Analysis

Song

Han

Liu

et al. 2020

Front. Mol. Biosci.

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Background: Coronavirus disease 2019 (COVID-19) was first detected in patients with pneumonia in December 2019 in China and it spread rapidly to the rest of the world becoming a global pandemic. Several observational studies have reported that cancer is a risk factor for COVID-19. On the other hand, ACE2, a receptor for the SARS-CoV-2 virus, was found to be aberrantly expressed in many tumors. However, the characterization of aberrant ACE2 expression in malignant tumors has not been elucidated. Here, we conducted a systematic analysis of the ACE2 expression profile across 31 types of tumors. Methods: Distribution of ACE2 expression was analyzed using the GTEx, CCLE, TCGA pan-cancer databases. We evaluated the effect of ACE2 on clinical prognosis using the Kaplan-Meier survival plot and COX regression analysis. Correlation between ACE2 and immune infiltration levels was investigated in various cancer types. Additionally, the correlation between ACE2 and immune neoantigen, TMB, microsatellite instability, Mismatch Repair Genes (MMRs), HLA gene members, and DNA Methyltransferase (DNMT) was investigated. The frequency of ACE2 gene mutation in various tumors was analyzed. Functional enrichment analysis was conducted in various cancer types using the GSEA method. Results: In normal tissues, ACE2 was highly expressed in almost all 31 organs tested. In cancer cell lines, the expression level of ACE2 was low to medium. Although aberrant expression was observed in most cancer types, high expression of ACE2 was not linked to OS, DFS, RFS, and DFI in most tumors in TCGA pan-cancer data. We found that ACE2 expression was significantly correlated with the infiltrating levels of macrophages and dendritic cells, CD4+ T cells, CD8+ T cells, and B cells in multiple tumors. A positive correlation between ACE2 expression and immune neoantigen, TMB, and microsatellite instability was found in multiple cancers. GSEA analysis which was

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“…In both studies, three companion assays-with 22C3 (used for pembrolizumab), 28-2 (used for nivolumab), and SP263 (used for durvalumab) antibody clones-achieved comparable specificity and sensitivity. Clone SP142, used for atezolizumab, was found to be less sensitive (37)(38)(39).…”

Section: Pd-l1 Expressionmentioning

confidence: 97%

Imperfect Predictors for Lung Cancer Immunotherapy—A Field for Further Research

Wojas‐Krawczyk

Kubiatowski

2020

Front. Oncol.

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The armamentarium for lung cancer immunotherapy has been strengthened using two groups of monoclonal antibodies: 1) anti-PD-1 antibodies, including pembrolizumab and nivolumab, which block the programmed death 1 receptor on the lymphocyte surface, resulting in increasing activity of these cells, and 2) anti-PD-L1 antibodies, including atezolizumab, durvalumab, and avelumab, which block the ligand for the PD-1 molecule on tumor cells and on tumor-infiltrating immune cells. The effectiveness of both groups of antibodies has been proven in many clinical trials, which translates into positive immunotherapeutic registrations for cancer patients. Regarding the predictive factor, PD-L1 expression on cancer cells is the only biomarker validated in prospective clinical trials used for qualification to immunotherapy in advanced non-small cell lung cancer (NSCLC) patients. However, it is not an ideal one. Unfortunately, no clinical benefits could be noted in patients with high PD-L1 expression on tumor cells against the effectiveness of immunotherapy that may be observed in patients without PD-L1 expression. Furthermore, the mechanism of antitumor immune response is extremely complex, multistage, and depends on many factors. Cancer cells could be recognized by the immune system, provided tumor-specific antigen presentation, and these arise as a result of somatic mutations in tumor cells. Based on novel immunotherapy registration, high tumor mutation burden (TMB) has become an important predictive factor. The intensity of lymphocyte infiltration in tumor tissue may be another predictive factor. The effectiveness of anti-PD-L1 immunotherapy is observed in patients with high expression of genes associated with the effector function of T lymphocytes (i.e., their ability to produce IFN-gamma). This does not end the list of potential factors that become useful in qualification of cancer patients for immunotherapy. There remains a need to search for new and perfect predictive factors for immunotherapy.

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Targeted literature review on use of tumor mutational burden status and programmed cell death ligand 1 expression to predict outcomes of checkpoint inhibitor treatment

Cited by 47 publications

References 55 publications

Clinical Implications of Aberrant PD-1 and CTLA4 Expression for Cancer Immunity and Prognosis: A Pan-Cancer Study

Clinical Implications of Aberrant PD-1 and CTLA4 Expression for Cancer Immunity and Prognosis: A Pan-Cancer Study

Systematic Analysis of Coronavirus Disease 2019 (COVID-19) Receptor ACE2 in Malignant Tumors: Pan-Cancer Analysis

Imperfect Predictors for Lung Cancer Immunotherapy—A Field for Further Research

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