Cytolytic Activity Score to Assess Anticancer Immunity in Colorectal Cancer

Narayanan, Sumana; Kawaguchi, Tsutomu; Yan, Li; Peng, Xuan; Qi, Qianya; Takabe, Kazuaki

doi:10.1245/s10434-018-6506-6

Cited by 113 publications

(118 citation statements)

References 49 publications

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“…Multiple studies have shown that infiltration of immune cells into the tumor microenvironment is a prognostic factor in cancer. Recent studies focusing on tumor immune cytolytic activity also demonstrated that transcript levels of two key cytolytic effectors, GZMA and PRF1 , correlate with patient survival . In this study, using transcriptome profiling data, we estimated immune cell composition and cytolytic activity in SCCOT, clinically tumor‐free tongue tissue from SCCOT patients and control tongue tissue from healthy individuals.…”

Section: Discussionmentioning

confidence: 99%

“…We also found that patients with high cytolytic activity in tumor‐free tongue had improved survival compared with patients with low cytolytic activity. Cytolytic activity in tumors has been shown to correlate with mutation load and number of predicted neoantigens . Oral SCC, including SCCOT, is a paradigm of Slaughter's concept of ‘field cancerization’ , in which tumors are thought to arise from an expanded pool of genetically altered pre‐neoplastic cells .…”

Section: Discussionmentioning

confidence: 99%

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High immune cytolytic activity in tumor‐free tongue tissue confers better prognosis in patients with squamous cell carcinoma of the oral tongue

Boldrup

Coates

et al. 2019

The Journal of Pathology CR

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Immune cells and cytolytic activity within the tumor microenvironment are being intensively studied. Through transcriptome profiling, immune cell enumeration using the xCell tool and cytolytic activity quantification according to granzyme A (GZMA) and perforin (PRF1) mRNA levels, we investigated immunoreactivity in tumor and/or tumor‐free tongue tissue samples from 31 patients with squamous cell carcinoma of the oral tongue and 14 healthy individuals (control tongue tissues). We found significantly altered immune cell compositions (p < 0.001) and elevated cytolytic activity (p < 0.001) in tumor compared to tumor‐free samples, and altered infiltration of a subset of immune cells (e.g. CD8+ T cells, p < 0.01) as well as increased cytolytic activity (p < 0.001) in tumor‐free compared to control samples. Controlling for patient age at diagnosis and tumor stage, Cox regression analysis showed that high cytolytic activity in tumor‐free samples associated with improved disease‐free survival (hazard ratio= 4.20, 95% CI = 1.09–16.20, p = 0.037). However, the degree of cytolytic activity in tumor samples did not provide prognostic information. Taken together, our results show the presence of cancer‐related immune responses in clinically tumor‐free tongue in patients with squamous cell carcinoma of the oral tongue. Measuring cytolytic activity in tumor‐free tongue samples contralateral to tumor might thus be an effective approach to predict clinical outcome.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

High immune cytolytic activity in tumor‐free tongue tissue confers better prognosis in patients with squamous cell carcinoma of the oral tongue

Boldrup

Coates

et al. 2019

The Journal of Pathology CR

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“…Tumor gene expression and corresponding clinical data for the TCGA-BRCA project were obtained from the Pan-Cancer Clinical Data Resource [39] and through cBio Cancer Genomic Portal [40], as we previously reported [41][42][43][44][45]. Data for the 1065 female patients were analyzed in the study.…”

Section: Data Of the Cancer Genome Atlas Breast Cancer Cohortmentioning

confidence: 99%

G2M Cell Cycle Pathway Score as a Prognostic Biomarker of Metastasis in Estrogen Receptor (ER)-Positive Breast Cancer

Oshi

Takahashi

Tokumaru

et al. 2020

IJMS

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The vast majority of breast cancer death is a result of metastasis. Thus, accurate identification of patients who are likely to have metastasis is expected to improve survival. The G2M checkpoint plays a critical role in cell cycle. We hypothesized that breast cancer tumors with high activity of G2M pathway genes are more aggressive and likely to metastasize. To test this, we used the single-sample gene set variation analysis method to calculate the score for the Hallmark G2M checkpoint pathway using gene expression data of a total of 4626 samples from 12 human breast cancer cohorts. As expected, a high G2M pathway score correlated with enriched tumor expression of other cell proliferation-related gene sets. The score was significantly associated with clinical aggressive features of tumors and patient survival in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Interestingly, a high G2M score of metastasis tumors was also significantly associated with worse survival. In primary as well as metastasis tumors with high scores, the infiltration of both pro- and anti-cancerous immune cells increased. Tumor G2M score was also associated with treatment response to systemic chemotherapy in ER-positive/HER2-negative cancer, and was predictive of response to cyclin-dependent kinase inhibition therapy.

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“…Measurements of immune activities like T cell receptor diversity and relative fractions in tumors of different types of immune cells were estimated from tumor gene expression with CIBERSORT, a bioinformatic algorithm 34 . Immune cytolytic activity in tumors was defined as the geometric mean of grandzyme A (GZMA) and Perforin 1 (PRF1) expression values in transcripts per million (TPM), as described previously 36,37 . In order to confirm correlation between CYT and grandzyme B (GZMB) or Interferon (IFN)-gamma, Spearman correlation was calculated, which demonstrated r = 0.819 (p < 0.01) and r = 0.789 (p < 0.01), respectively ( Supplementary Fig.S1).…”

Section: Analysis Of Gene Expression Datamentioning

confidence: 99%

Biologically Aggressive Phenotype and Anti-cancer Immunity Counterbalance in Breast Cancer with High Mutation Rate

Takahashi

Asaoka

Yan

et al. 2020

Sci Rep

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While cancer cells gain aggressiveness by mutations, abundant mutations release neoantigens, attracting anti-cancer immune cells. We hypothesized that in breast cancer (BC), where mutation is less common, tumors with high mutation rates demonstrate aggressive phenotypes and attract immune cells simultaneously. High mutation rates were defined as the top 10% of the mutation rate, utilizing TCGA and METABRIC transcriptomic data. Mutation rate did not impact survival although high mutation BCs were associated with aggressive clinical features, such as more frequent in ER-negative tumors (p < 0.01), in triple-negative subtype (p = 0.03), and increased MKI-67 mRnA expression (p < 0.01) in both cohorts. Tumors with high mutation rates were associated with APOBEC3B and homologous recombination deficiency, increasing neoantigen loads (all p < 0.01). Cell proliferation and immune activity pathways were enriched in BCs with high mutation rates. Furthermore, there were higher lymphocytes and M1 macrophage infiltration in high mutation BCs. Additionally, T-cell receptor diversity, cytolytic activity score (CYT), and T-cell exhaustion marker expression were significantly elevated in BCs with high mutation rates (all p < 0.01), indicating strong immunogenicity. In conclusion, enhanced immunity due to neoantigens can be one of possible forces to counterbalance aggressiveness of a high mutation rate, resulting in similar survival rates to low mutation BCs. Accumulation of somatic mutations, or somatic genome instability, has been the principle of carcinogenesis; cancer cells stem from a clone that has gained the somatically acquired genetic abnormalities, leading to malignant transformation and further progression 1. With advances in next-generation sequencing technologies, clinical interest in assessing mutation burden and identifying specific mutations in certain cancer types has been growing to utilize targeted therapies or to assess tumor biology, such as FoundationOne genomic panel testing 2-4. Mutation rates are variable among cancer types and outliers with significantly high mutation burdens, hypermutation, do exist in many cancer types 5. Interestingly, the definition of hypermutation has been variable in the literature 5-7 , although the common definition is usually greater than 10-100 mutations per Mega base pairs (Mbps). Campbell and colleagues recently performed comprehensive analysis of hypermutation in various tumor types, providing more insight into tumor evolution and identifying possible clinically actionable mutation signatures 6. The etiology of hypermutation varies between cancer types; ultraviolet (UV) light is the significant cause of mutations in melanoma, while smoking causes the mutations in non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (SCC) 7,8. Whereas UV light and smoking are examples of exogenous mutagens, there are endogenous processes for mutation, such as microsatellite instability (MSI), and Apolipoprotein

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Cytolytic Activity Score to Assess Anticancer Immunity in Colorectal Cancer

Cited by 113 publications

References 49 publications

High immune cytolytic activity in tumor‐free tongue tissue confers better prognosis in patients with squamous cell carcinoma of the oral tongue

High immune cytolytic activity in tumor‐free tongue tissue confers better prognosis in patients with squamous cell carcinoma of the oral tongue

G2M Cell Cycle Pathway Score as a Prognostic Biomarker of Metastasis in Estrogen Receptor (ER)-Positive Breast Cancer

Biologically Aggressive Phenotype and Anti-cancer Immunity Counterbalance in Breast Cancer with High Mutation Rate

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