Tumor-infiltrating Lymphocytes Predict the Chemotherapeutic Outcomes in Patients with Stage IV Colorectal Cancer

Shibutani, Masatsune; Maeda, Kiyoshi; Nagahara, Hisashi; Fukuoka, Tatsunari; Iseki, Yasuhito; Matsutani, Shinji; Kashiwagi, Shinichiro; Tanaka, Hiroaki; Hirakawa, Kosei; Ohira, Masaichi

doi:10.21873/invivo.11218

Cited by 34 publications

(22 citation statements)

References 28 publications

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“…Thus, the density of TILs in the primary tumor may be a surrogate marker for the density of TILs in the metastatic tumor. The results obtained in this study support the claim that the local immune status of the primary tumor is associated with the efficacy of the chemotherapy, which was reported in our previous report [ 22 ]. It may be possible to predict the chemotherapeutic efficacy on the metastatic tumor by evaluating the density of TILs in the primary tumor, even if the local immune status of the metastatic tumor cannot be evaluated.…”

Section: Discussionsupporting

confidence: 92%

A comparison of the local immune status between the primary and metastatic tumor in colorectal cancer: a retrospective study

et al. 2018

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BackgroundThe anticancer immune response has been reported to correlate with cancer progression. Tumor-infiltrating lymphocytes (TILs), which are one of the indicators of host immunity, affect the tumor growth, metastasis and chemoresistance. Both TILs in the primary tumor and those in the metastatic tumor have been reported to be a useful predictor of the survival and therapeutic outcome. However, the correlation between the density of TILs in the primary and metastatic tumor is unclear. The aim of this study was to elucidate the correlation between the density of TILs in the primary and metastatic tumor.MethodsA total of 24 patients with stage IV colorectal cancer who underwent concurrent resection of the primary tumor and liver metastasis were enrolled in order to assess the correlation between the density of TILs in the primary tumor and that in the metastatic tumor. Hematoxylin and eosin (HE)-stained tumor sections were used for the evaluation of TILs. The density of TILs was assessed by the measurement of the area occupied by mononuclear inflammatory cells over the total stromal area at the invasive margin. In addition, to evaluate TIL subsets and the activation/suppression status of the lymphocytes, immunohistochemistry for CD4, CD8, Forkhead boxprotein P3 (FOXP3), programmed cell death 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), inducible T-cell co-stimulator (ICOS), Glucocorticoid induced tumor necrosis factor receptor related protein (GITR), Human Leukocyte Antigen - antigen D Related (HLA-DR) and Granzyme B was performed, and the number of immunoreactive lymphocytes was counted.ResultsAccording to the evaluation using the HE-stained sections, the density of tumor-infiltrating mononuclear inflammatory cells in the primary tumor was significantly associated with that in the metastatic tumor. In addition, according to the immunohistochemistry evaluation, the density of CD4+, CD8+ and FOXP3+ TILs in the primary tumor and that in the metastatic tumor were significantly correlated with that in the metastatic tumor. Furthermore, the activation/suppression marker values of the lymphocytes (i.e., such as PD-1, ICOS, Granzyme B and the PD-1/CD8 ratio) in the primary tumor were correlated with values in the metastatic tumor.ConclusionsThe local immune status of the primary tumor was revealed to be similar to that of the metastatic tumor. This suggests that the evaluation of the local immunity of the primary tumor may be a substitute for the evaluation of the local immunity of the metastatic lesion. Therefore, information on the primary tumor may be useful when considering treatment strategies for metastatic lesions.

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Section: Discussionsupporting

confidence: 92%

A comparison of the local immune status between the primary and metastatic tumor in colorectal cancer: a retrospective study

et al. 2018

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“…Of note, in the high-TILs group a significantly better OS was observed compared to low-TILs group (35.5 months vs. 22.4 months, p = 0.022). 28 Taken together, data on TILs and CMS suggest a role for tumour-immune system interaction in affecting prognosis of V600E BRAF mutated mCRC.…”

Section: Discussionmentioning

confidence: 96%

CK7 and consensus molecular subtypes as major prognosticators in V600EBRAF mutated metastatic colorectal cancer

et al. 2019

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Background V600E BRAF mutated metastatic colorectal cancer (mCRC) is a subtype (10%) with overall poor prognosis, but the clinical experience suggests a great heterogeneity in survival. It is still unexplored the real distribution of traditional and innovative biomarkers among V600E BRAF mutated mCRC and which is their role in the improvement of clinical prediction of survival outcomes. Methods Data and tissue specimens from 155 V600E BRAF mutated mCRC patients treated at eight Italian Units of Oncology were collected. Specimens were analysed by means of immunohistochemistry profiling performed on tissue microarrays. Primary endpoint was overall survival (OS). Results CDX2 loss conferred worse OS (HR = 1.72, 95%CI 1.03–2.86, p = 0.036), as well as high CK7 expression (HR = 2.17, 95%CI 1.10–4.29, p = 0.026). According to Consensus Molecular Subtypes (CMS), CMS1 patients had better OS compared to CMS2-3/CMS4 (HR = 0.37, 95%CI 0.19–0.71, p = 0.003). Samples showing less TILs had worse OS (HR = 1.72, 95%CI 1.16–2.56, p = 0.007). Progression-free survival analyses led to similar results. At multivariate analysis, CK7 and CMS subgrouping retained their significant correlation with OS. Conclusion The present study provides new evidence on how several well-established biomarkers perform in a homogenous V600E BRAF mutated mCRC population, with important and independent information added to standard clinical prognosticators. These data could be useful to inform further translational research, for patients’ stratification in clinical trials and in routine clinical practice to better estimate patients’ prognosis.

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“…Then, downloaded samples and corresponding clinical data were cross-referenced by TCGA barcodes. Some patients do not meet the following criteria were eliminated: [ 1 ] a histological diagnosis of CRC [ 2 ] patients with complete clinical features including sex, age, tumor location, local invasion, lymph node metastasis, distal metastasis, differentiation grade, pathologic stage, survival information; [ 3 ] patients were still alive at least 1 month after initial pathologic diagnosis; [ 4 ] patients with corresponding RNA-Seq data. To generate the AS profiles for each CRC patient, SpliceSeq, a java application that unambiguously quantify the inclusion level of each exon and splice junction, was used to evaluate the RNA splicing patterns as previous described [ 26 , 27 ].…”

Section: Methodsmentioning

confidence: 99%

“…At present, surgical resection is the only potentially curative therapy for CRC. Unfortunately, about 20–25% of patients with newly diagnosed CRC present with distant metastases, and only a small population of these patients can undergo curative operation [ 3 ]. More seriously, approximately 50% of CRC patients with resectable tumors will develop recurrence, most within 2 years [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Profiles of alternative splicing in colorectal cancer and their clinical significance: A study based on large-scale sequencing data

et al. 2018

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BackgroundAlternative splicing (AS), as a potent and pervasive mechanism of transcriptional regulatory, expands the genome's coding capacity and involves in the initiation and progression of cancer. Systematic analysis of alternative splicing in colorectal cancer (CRC) is lacking and greatly needed.MethodsRNA-Seq data and corresponding clinical information of CRC cohort were downloaded from the TCGA data portal. Then, a java application, known as SpliceSeq, was used to evaluate the RNA splicing patterns and calculate the Percent Spliced In (PSI) value. Differently expressed AS events (DEAS) were identified based on PSI value between paired CRC and adjacent tissues. DEAS and its splicing networks were further analyzed by bioinformatics methods. Kaplan-Meier, Cox proportional regression and unsupervised clustering analysis were used to evaluate the association between DEAS and patients' clinical features.ResultsAfter strict filtering, a total of 34,334 AS events were identified, among which 421 AS events were found expressed differently. Parent genes of these DEAS play a important role in regulating CRC-related processes such as protein kinase activity (FDR<0.0001), PI3K-Akt signaling pathway (FDR = 0.0024) and p53 signaling pathway (FDR = 0.0143). 37 DEAS events were found to be associated with OS, and 68 DEAS events were found to be associated with DFS. Stratifying patients according to the PSI value of AT in CXCL12 and RI in CSTF3 formed significant Kaplan-Meier curves in both OS and DFS survival analysis. Unsupervised clustering analysis using DEAS revealed four clusters with distinct survival patterns, and associated with consensus molecular subtypes.ConclusionsLarge differences of AS events in CRC appear to exist, and these differences are likely to be important determinants of both prognosis and biological regulation. Our identified CRC-related AS events and uncovered splicing networks are valuable in deciphering the underlying mechanisms of AS in CRC, and provide clues of therapeutic targets to further validations.

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Tumor-infiltrating Lymphocytes Predict the Chemotherapeutic Outcomes in Patients with Stage IV Colorectal Cancer

Cited by 34 publications

References 28 publications

A comparison of the local immune status between the primary and metastatic tumor in colorectal cancer: a retrospective study

A comparison of the local immune status between the primary and metastatic tumor in colorectal cancer: a retrospective study

CK7 and consensus molecular subtypes as major prognosticators in V600EBRAF mutated metastatic colorectal cancer

Profiles of alternative splicing in colorectal cancer and their clinical significance: A study based on large-scale sequencing data

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