Dataset Information

Active secretion of CXCL10 and CCL5 from colorectal cancer microenvironments associates with GranzymeB+ CD8+ T-cell infiltration.

ABSTRACT: Transcriptional expression of CXCR3 and CCR5 cognate chemokines correlate with CD8+ T-cell infiltration and prolonged survival in colorectal cancer (CRC). These findings were derived mainly from paraffin embedded tissues; thus little is known about the secretion pattern of CD8+ T-cell targeting chemokines from CRCs. Therefore, we developed and introduced a novel platform that assesses the immune mediators that are secreted from live excised tissues. Transcriptional profiling and unsupervised hierarchical clustering of 43 CRCs based on expression of genes that represent the adaptive immune response were used to predict tumors that are strong secretors of T-cell targeting chemokines. Secretion of these mediators were corroborated using flow cytometric analysis of T-cell lineage markers: CD4, CD8, IFN-?, and GzmB. We demonstrate that stronger secretion of CXCL10 (CXCR3 ligand) and CCL5 (CCR5 ligand) and infiltration of GzmB+CD8+ cytotoxic T-lymphocytes (CTLs) and IFN-?+CD4+ helper T-cells can be predicted by transcriptional profiling, and that CRCs with stronger T-cell immunity were proportionally skewed towards early TNM stages and lacked distant organ metastasis. Our study represents the first functional analysis of secreted immune mediators from CRCs beyond immunohistochemistry and real-time PCR, and observed active physiological interactions between the tumor cells and the immune cells in the tumor microenvironment.

SUBMITTER: Zumwalt TJ

PROVIDER: S-EPMC4413778 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Active secretion of CXCL10 and CCL5 from colorectal cancer microenvironments associates with GranzymeB+ CD8+ T-cell infiltration.

Zumwalt Timothy J TJ Arnold Mildred M Goel Ajay A Boland C Richard CR

Oncotarget 20150201 5

Transcriptional expression of CXCR3 and CCR5 cognate chemokines correlate with CD8+ T-cell infiltration and prolonged survival in colorectal cancer (CRC). These findings were derived mainly from paraffin embedded tissues; thus little is known about the secretion pattern of CD8+ T-cell targeting chemokines from CRCs. Therefore, we developed and introduced a novel platform that assesses the immune mediators that are secreted from live excised tissues. Transcriptional profiling and unsupervised hie ...[more]

PMID: 25671296

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Project description:Background and purpose: Combining inhibitors of vascular endothelial growth factor and the programmed cell death protein 1 (PD1) pathway has shown efficacy in multiple cancers, but the disease-specific and agent-specific mechanisms of benefit remain unclear. We examined the efficacy and defined the mechanisms of benefit when combining regorafenib (a multikinase antivascular endothelial growth factor receptor inhibitor) with PD1 blockade in murine hepatocellular carcinoma (HCC) models.Basic procedures: We used orthotopic models of HCC in mice with liver damage to test the effects of regorafenib-dosed orally at 5, 10 or 20?mg/kg daily-combined with anti-PD1 antibodies (10?mg/kg intraperitoneally thrice weekly). We evaluated the effects of therapy on tumor vasculature and immune microenvironment using immunofluorescence, flow cytometry, RNA-sequencing, ELISA and pharmacokinetic/pharmacodynamic studies in mice and in tissue and blood samples from patients with cancer.Main findings: Regorafenib/anti-PD1 combination therapy increased survival compared with regofarenib or anti-PD1 alone in a regorafenib dose-dependent manner. Combination therapy increased regorafenib uptake into the tumor tissues by normalizing the HCC vasculature and increasing CD8 T-cell infiltration and activation at an intermediate regorafenib dose. The efficacy of regorafenib/anti-PD1 therapy was compromised in mice lacking functional T cells (Rag1-deficient mice). Regorafenib treatment increased the transcription and protein expression of CXCL10-a ligand for CXCR3 expressed on tumor-infiltrating lymphocytes-in murine HCC and in blood of patients with HCC. Using Cxcr3-deficient mice, we demonstrate that CXCR3 mediated the increased intratumoral CD8 T-cell infiltration and the added survival benefit when regorafenib was combined with anti-PD1 therapy.Principal conclusions: Judicious regorafenib/anti-PD1 combination therapy can inhibit tumor growth and increase survival by normalizing tumor vasculature and increasing intratumoral CXCR3+CD8?T-cell infiltration through elevated CXCL10 expression in HCC cells.

Project description:BACKGROUND AND AIMS: Reliable prognostic markers based on biopsy specimens of colorectal cancer (CRC) are currently missing. We hypothesize that assessment of T-cell infiltration in biopsies of CRC may predict patient survival and TNM-stage before surgery. METHODS: Pre-operative biopsies and matched resection specimens from 130 CRC patients treated from 2002-2011 were included in this study. Whole tissue sections of biopsy material and primary tumors were immunostained for pancytokeratin and CD8 or CD45RO. Stromal (s) and intraepithelial (i) T-cell infiltrates were analyzed for prediction of patient survival as well as clinical and pathological TNM-stage of the primary tumor. RESULTS: CD8 T-cell infiltration in the preoperative biopsy was significantly associated with favorable overall survival (CD8i p?=?0.0026; CD8s p?=?0.0053) in patients with primary CRC independently of TNM-stage and postoperative therapy (HR [CD8i]?=?0.55 (95% CI: 0.36-0.82), p?=?0.0038; HR [CD8s]?=?0.72 (95% CI: 0.57-0.9), p?=?0.0049). High numbers of CD8i in the biopsy predicted earlier pT-stage (p?<?0.0001) as well as absence of nodal metastasis (p?=?0.0015), tumor deposits (p?=?0.0117), lymphatic (p?=?0.008) and venous invasion (p?=?0.0433) in the primary tumor. Infiltration by CD45ROs cells was independently associated with longer survival (HR?=?0.76 (95% CI: 0.61-0.96), p?=?0.0231) and predicted absence of venous invasion (p?=?0.0025). CD8 counts were positively correlated between biopsies and the primary tumor (r?=?0.42; p?<?0.0001) and were reproducible between observers (ICC [CD8i]?=?0.95, ICC [CD8s]?=?0.75). For CD45RO, reproducibility was poor to moderate (ICC [CD45i]?=?0.16, ICC [CD45s]?=?0.49) and correlation with immune infiltration in the primary tumor was fair and non-significant (r[CD45s]?=?0.16; p?=?0.2864). For both markers, no significant relationship was observed with radiographic T-stage, N-stage or M-stage, indicating that assessment of T-cells in biopsy material can add additional information to clinical staging in the pre-operative setting. CONCLUSIONS: T-cell infiltration in pre-operative biopsy specimens of CRC is an independent favorable prognostic factor and strongly correlates with absence of nodal metastasis in the resection specimen. Quantification of CD8i is highly reproducible and allows superior prediction of clinicopathological features as compared to CD45RO. The assessment of CD8i infiltration in biopsies is recommended for prospective investigation.

Dataset Information

Active secretion of CXCL10 and CCL5 from colorectal cancer microenvironments associates with GranzymeB+ CD8+ T-cell infiltration.

Publications

Active secretion of CXCL10 and CCL5 from colorectal cancer microenvironments associates with GranzymeB+ CD8+ T-cell infiltration.

Similar Datasets

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