TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor <i>CD274</i> (PD-L1) expression status and tumor-infiltrating lymphocytes in colorectal carcinomas

Hamada, Tsuyoshi; Soong, Thing Rinda; Masugi, Yohei; Kosumi, Keisuke; Nowak, Jonathan A.; Silva, Annacarolina da; Mu, Xinmeng Jasmine; Twombly, Tyler S.; Koh, Hideo; Yang, Juhong; Song, Mingyang; Liu, Li; Gu, Mancang; Shi, Yan; Nosho, Katsuhiko; Morikawa, Teppei; Inamura, Kentaro; Shukla, Sachet A.; Wu, Catherine J.; Garraway, Levi A.; Zhang, Xuehong; Wu, Kana; Meyerhardt, Jeffrey A.; Chan, Andrew T.; Glickman, Jonathan N.; Rodig, Scott J.; Freeman, Gordon J.; Fuchs, Charles S.; Nishihara, Reiko; Giannakis, Marios; Ogino, Shuji

doi:10.1080/2162402x.2018.1442999

Cited by 61 publications

(47 citation statements)

References 66 publications

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“…The inter‐patient and inter‐tissue variability of PD‐L1 by our IHC detection demonstrates that the expression of PD‐L1 may differ between different lung cancer cohorts, and may be influenced by various factors, including tumor types, genetic backgrounds, and inflammation. It was reported that TMIT stratification of colorectal cancer was associated with high levels of microsatellite instability and neoantigen load, supporting better response to ICI . However, the analysis was based on the TILs counting in both tumor and adjacent stroma together.…”

Section: Discussionmentioning

confidence: 99%

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The landscape of immune microenvironment in lung adenocarcinoma and squamous cell carcinoma based on PD‐L1 expression and tumor‐infiltrating lymphocytes

et al. 2019

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Aims The aim of this study was to investigate the tumor microenvironment immune types (TMIT) based on tumor cell programmed cell death ligand 1 (PD‐L1) expression and tumor‐infiltrating lymphocytes (TILs) distribution and whether distinct TMIT subtypes (TMIT I, PD‐L1high/TILhigh; TMIT II, PD‐L1low/TILlow; TMIT III, PD‐L1high/TILlow; and TMIT IV, PD‐L1low/TILhigh) differentially affect clinical outcomes of patients with lung adenocarcinoma (LAC) and squamous cell carcinoma (SCC). Methods and results Immunohistochemistry (IHC) was applied to evaluate the expression of PD‐L1 and the spatial distribution of programmed cell death 1 (PD‐1) and CD8 TILs on the surgically resected specimens from 205 cases of LAC and 149 cases of SCC. PD‐1 and CD8 TILs were more frequently distributed in SCC than those in LAC, regardless of their infiltrating in the tumor islets or stroma. The density of TILs was a poor prognostic factor in LAC but a favorable one in SCC. PD‐L1 levels and its clinical prognostic significance differed in LAC vs SCC. LAC patients with TMIT III and SCC patients with TMIT I had the longest survival, respectively (P = .0197 and .0049). Moreover, TMIT stratification based on tumor cell PD‐L1 expression and stromal CD8+ TILs could be considered as an independent prognostic factor of SCC patients' survival as determined by both univariate and multivariate analysis. Conclusion Our study indicates that different type of TMIT provides its specific microenvironment with diverse impact on survival of LAC and SCC patients and highlights the importance of the integrative assessment of PD‐L1 status and TILs' spatial distribution to predict patients' prognosis.

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Section: Discussionmentioning

confidence: 99%

“…It was reported that TMIT stratification of colorectal cancer was associated with high levels of microsatellite instability and neoantigen load, supporting better response to ICI. 29 However, the analysis .059…”

Section: Discussionmentioning

confidence: 99%

The landscape of immune microenvironment in lung adenocarcinoma and squamous cell carcinoma based on PD‐L1 expression and tumor‐infiltrating lymphocytes

et al. 2019

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“…Immunotherapy, as a tool for cancer management, has gained significant importance. Additionally, activation of immune system and subsequent immune reaction play an important role in tumor microenvironment in suppressing tumor development and progression [147] . The presence of TILS provides evidence that the host's immune system is attempting to eliminate the tumor, and this is an important favorable prognostic factor in CRC [148] , [149] .…”

Section: Discussionmentioning

confidence: 99%

Clinical, Pathological, and Molecular Characteristics of CpG Island Methylator Phenotype in Colorectal Cancer: A Systematic Review and Meta-analysis

Advani

DeSantis

et al. 2018

Translational Oncology

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BACKGROUND: CpG island methylator phenotype (CIMP) tumors, comprising 20% of colorectal cancers, are associated with female sex, age, right-sided location, and BRAF mutations. However, other factors potentially associated with CIMP have not been robustly examined. This meta-analysis provides a comprehensive assessment of the clinical, pathologic, and molecular characteristics that define CIMP tumors. METHODS: We conducted a comprehensive search of the literature from January 1999 through April 2018 and identified 122 articles, on which comprehensive data abstraction was performed on the clinical, pathologic, molecular, and mutational characteristics of CIMP subgroups, classified based on the extent of DNA methylation of tumor suppressor genes assessed using a variety of laboratory methods. Associations of CIMP with outcome parameters were estimated using pooled odds ratio or standardized mean differences using random-effects model. RESULTS: We confirmed prior associations including female sex, older age, right-sided tumor location, poor differentiation, and microsatellite instability. In addition to the recognized association with BRAF mutations, CIMP was also associated with PIK3CA mutations and lack of mutations in KRAS and TP53. Evidence of an activated immune response was seen with high rates of tumor-infiltrating lymphocytes (but not peritumoral lymphocytes), Crohn-like infiltrates, and infiltration with Fusobacterium nucleatum bacteria. Additionally, CIMP tumors were associated with advance T-stage and presence of perineural and lymphovascular invasion. CONCLUSION: The meta-analysis highlights key features distinguishing CIMP in colorectal cancer, including molecular characteristics of an active immune response. Improved understanding of this unique molecular subtype of colorectal cancer may provide insights into prevention and treatment.

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“…3 The mismatch repair (MMR)/microsatellite instability (MSI) pathway significantly contributes to CRC development 12,13 and is associated with the immune microenvironment. 14,15 However, although the distinct features of MSI-high (MSI-H) tumors have been identified, 16 MSI status of the primary CRC versus its metastatic lesions has not been fully explored. Change in MSI status is important because studies have shown that only patients with deficient MMR (dMMR) or MSI-high tumors benefit from anti-PD-1 therapy.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Mismatch Repair Status Between Primary and Matched Metastatic Sites in Patients With Colorectal Cancer

Wang¹,

Wang

et al. 2019

Journal of the National Comprehensive Cancer Network

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Background: Differences between the features of primary cancer and matched metastatic cancer have recently drawn attention in research. This study investigated the concordance in microsatellite instability (MSI) and mismatch repair (MMR) status between primary and corresponding metastatic colorectal cancer (CRC). Methods: Consecutive patients with metastatic CRC who had both primary and metastatic tumors diagnosed at our institution in January 2008 through December 2016 were identified. Immunohistochemistry was used to test the MMR status of both primary and matched metastatic tumors, and PCR analysis was performed to test MSI in patients with deficient MMR (dMMR) status. Results: A total of 369 patients were included. Of the 46 patients with MSI-high primary tumors, 37 (80.4%) also had MSI-high metastatic tumors, whereas 9 (19.6%) had microsatellite stable (MSS) metastatic tumors. A high concordance was found in patients with liver, lung, or distant lymph node metastases. Interestingly, the discrepancy was more likely to be limited to peritoneal (5/20) or ovarian (4/4) metastasis (chi-square test, P<.001). These organ-specific features were also found in the pooled analysis. Along with the change of MSI-high in primary cancer to MSS in metastatic cancer, lymphocyte infiltration decreased significantly (P=.008). However, the change did not influence survival; the median overall survival of MSI-high and MSS metastatic tumors was 21.3 and 21.6 months, respectively (P=.774). The discrepancy rate was 1.6% for patients with proficient MMR primary tumors. Conclusions: For patients with dMMR primary tumors, the concordance of MSI and MMR status in primary CRC and corresponding metastatic cancer is potentially organ-specific. High concordance is found in liver, lung, and distant lymph node metastases, whereas discrepancy is more likely to occur in peritoneal or ovarian metastasis. Rebiopsy to evaluate MSI-high/dMMR status might be needed during the course of anti–PD-1 therapy in cases of peritoneal or ovarian metastasis.

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TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 (PD-L1) expression status and tumor-infiltrating lymphocytes in colorectal carcinomas

Cited by 61 publications

References 66 publications

The landscape of immune microenvironment in lung adenocarcinoma and squamous cell carcinoma based on PD‐L1 expression and tumor‐infiltrating lymphocytes

The landscape of immune microenvironment in lung adenocarcinoma and squamous cell carcinoma based on PD‐L1 expression and tumor‐infiltrating lymphocytes

Clinical, Pathological, and Molecular Characteristics of CpG Island Methylator Phenotype in Colorectal Cancer: A Systematic Review and Meta-analysis

Comparison of Mismatch Repair Status Between Primary and Matched Metastatic Sites in Patients With Colorectal Cancer

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