scholarly journals Versican-Derived Matrikines Regulate Batf3–Dendritic Cell Differentiation and Promote T Cell Infiltration in Colorectal Cancer

2017 ◽  
Vol 199 (5) ◽  
pp. 1933-1941 ◽  
Author(s):  
Chelsea Hope ◽  
Philip B. Emmerich ◽  
Athanasios Papadas ◽  
Adam Pagenkopf ◽  
Kristina A. Matkowskyj ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Differentiation ◽  
T Cell ◽  
Dendritic Cell ◽  
Cell Infiltration ◽  
Dendritic Cell Differentiation ◽  
T Cell Infiltration

scholarly journals 342 Combining enadenotucirev and nivolumab increased tumour immune cell infiltration/activation in patients with microsatellite-stable/instability-low metastatic colorectal cancer in a phase 1 study

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A368-A369
Author(s):  
David Krige ◽  
Marwan Fakih ◽  
Lee Rosen ◽  
Ding Wang ◽  
Wael Harb ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Metastatic Colorectal Cancer ◽  
Cd8 T Cell ◽  
Post Treatment ◽  
Institutional Review Board ◽  
Cell Infiltration ◽  
Link Type ◽  
T Cell Infiltration ◽  
Institutional Review

BackgroundMicrosatellite-stable (MSS) and instability-low (MSI-L) metastatic colorectal cancer (mCRC) are typically characterised as ”immune-excluded/desert” tumour microenvironments lacking T-cell infiltration. Anti-PD-1 monotherapy has little clinical benefit in MSS/MSI-L mCRC1 and knowledge of the effects of PD-1 inhibition on T-cell activation/infiltration in this population is limited. Novel combination therapies to overcome anti-PD-1 resistance are required. SPICE is a multicentre, open-label, phase 1 study of the tumour-selective chimeric Ad11/Ad3 group B oncolytic adenovirus enadenotucirev plus nivolumab in patients with metastatic/advanced epithelial tumours refractory to standard therapy. Preliminary data from patients with MSS/MSI-L mCRC demonstrated a median overall survival of 14 months, manageable tolerability and intratumoural T-cell infiltration.2 Here we characterise the immunological effects of tumour re-engineering with enadenotucirev in combination with nivolumab in patients with MSS/MSI-L mCRC.MethodsPatients received increasing doses and/or cycles of intravenous enadenotucirev followed by up to 8 cycles of nivolumab as previously described.2 Wherever possible, pre- and post-treatment (~5 weeks post-first enadenotucirev) biopsies were collected; samples were analysed using immunohistochemistry and automated image analysis. Peripheral blood mononuclear cell immunophenotyping (multiparameter flow cytometry) and serum cytokines were assessed at multiple times.Results43 patients with mCRC were treated (86% MSS/MSI-L; 14% unknown). Among the 13 patients (12/13 MSS/MSI-L; 1/13 unknown) with matched biopsies, 11 had increased intratumoural and stromal CD8+ T-cell infiltration in post-treatment biopsies (median [Q1-Q3] fold changes 6.5× [1.5–25.4] and 1.9× [1.5–3.9], respectively; figure 1). CD4+ T-cell density increased in 10/13 patients and 8/13 patients had increased proportions of PD-L1+ immune cells. Increases in CD8 T-cell proliferation (Ki67; 7/9 patients) and cytolytic activity (Granzyme B; 7/13 patients) markers were seen. 4/13 patients converted from a ”desert” to an ”inflamed” immune phenotype (pathologist scored CD8/pan-cytokeratin staining). Immunophenotyping showed trends towards increased T-cell activation (CD38+ and HLA-DR+ CD8+ T cell populations) post-treatment (9/10 patients), including in one patient who had only received enadenotucirev prior to sampling. Persistent increases in inflammatory cytokines (IFNγ, IL-12p70, IL-17a) were seen in two patients from ~Day 15, including one who achieved a sustained objective response.Abstract 342 Figure 1Tumour immune cell infiltration following treatment with enadenotucirev plus nivolumabConclusionsThese data show that intravenous enadenotucirev plus nivolumab can induce immune infiltration/activation within MSS/MSI-L mCRC. These encouraging findings suggest that immune activation can be achieved even in ”immune-excluded/desert” tumours. SPICE has been closed following completion of dose-escalation. Efforts are now focused on the development of next-generation variants of enadenotucirev designed to further re-programme the tumour microenvironment by expressing immune-enhancer transgenes (T-SIGn vectors); these studies are ongoing (NCT04830592, NCT04053283, NCT03852511).AcknowledgementsThis study was funded by PsiOxus Therapeutics Limited and Bristol Myers Squibb. Medical writing support: Lola Parfitt, MRes, of PsiOxus Therapeutics Limited.Trial RegistrationEudraCT number2017-001231-39NCT number: NCT02636036ReferencesKawazoe A, Kuboki Y, Shinozaki E, et al. Multicenter phase I/II trial of napabucasin and pembrolizumab in patients with metastatic colorectal cancer (EPOC1503/SCOOP trial). Clin Cancer Res 2020;26:5887–5894.Fakih M, Wang D, Harb W, et al. SPICE: a phase I multicenter study of enadenotucirev in combination with nivolumab in tumors of epithelial origin: an analysis of the metastatic colorectal cancer patients in the dose escalation phase. Ann Oncol 2019:30(suppl_5):v252.Ethics ApprovalThe study was approved by the WCG Institutional Review Board (study approval number 20152656), UCLA Institutional Review Board (study approval number IRB#15-002010), Vanderbilt Institutional Review Board (study approval number IRB #171453) and Henry Ford Institutional Review Board (study approval number IRB #10349).

scholarly journals Intrinsic β-catenin signaling suppresses CD8+ T-cell infiltration in colorectal cancer

2019 ◽  
Vol 115 ◽  
pp. 108921 ◽  
Author(s):  
Junli Xue ◽  
Xuetao Yu ◽  
Liqiong Xue ◽  
Xiaoxiao Ge ◽  
Wei Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
T Cell Infiltration

scholarly journals The Cationic Antimicrobial Peptide LL-37 Modulates Dendritic Cell Differentiation and Dendritic Cell-Induced T Cell Polarization

2004 ◽  
Vol 172 (2) ◽  
pp. 1146-1156 ◽  
Author(s):  
Donald J. Davidson ◽  
Andrew J. Currie ◽  
Gregor S. D. Reid ◽  
Dawn M. E. Bowdish ◽  
Kelly L. MacDonald ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
Dendritic Cell ◽  
Antimicrobial Peptide ◽  
Cell Polarization ◽  
Cationic Antimicrobial Peptide ◽  
Dendritic Cell Differentiation ◽  
T Cell Polarization

Su2037 CD8+ T-Cell Infiltration in Epithelial and Stromal Tissues of MSI Colorectal Cancer Patients

2016 ◽  
Vol 150 (4) ◽  
pp. S617
Author(s):  
Lakshmi Kannan ◽  
Hassan Ashktorab ◽  
Edward L. Lee ◽  
Babak Shokrani ◽  
Akbar Soleimani ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Cancer Patients ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Colorectal Cancer Patients

Predicting CD8+ T-cell infiltration in colorectal cancer using versican proteolysis across molecular profiles.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 189-189
Author(s):  
Katherine Anne Johnson ◽  
Philip Emmerich ◽  
Kristina A. Matkowskyj ◽  
Dustin A. Deming
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Tumor Infiltrating Lymphocytes ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Molecular Profile ◽  
High Power Field ◽  
Kras Mutations ◽  
T Cell Infiltration ◽  
The Impact

189 Background: The clinical indications for immunotherapies continue to increase across cancer types. In colorectal cancer (CRC), there has been little progress in the use of these therapies outside of mismatch repair deficient cancers (dMMR). However, even in dMMR cancers only a minority actually respond to the FDA-approved anti-PD1 agents. The tumor microenvironment is increasingly implicated in the resistance of cancers to immune-based therapies. Our group has previously described that accumulation of a matrix proteoglycan, versican, correlates with a reduction in CD8+ T-cell infiltration in CRCs, while proteolysis of versican, releasing the bioactive fragment versikine, correlates with increased infiltration. Here we examine the impact of pathogenic mutations on the utility of MMR status and versican proteolysis to predict CD8+ T-cell infiltration. Methods: Matched normal colon and CRC tissues from 122 patients were stained for versican, versikine, MLH1, MSH2, MSH6, PMS2, CNNB1, and CD8. Each was reviewed by a blinded GI surgical pathologist and CD8 quantified as tumor infiltrating lymphocytes (TILs) per high power field (hpf). 107 of the CRC samples were available for sequencing using the Qiagen Comprehensive Cancer Panel examining 160 genes across cancer relevant hotspots. The molecular profile was correlated with the IHC staining. Results: As previously reported, dMMR tumors had higher CD8+ T-cell infiltration. This trend persisted across dMMR genotypes (dMMR vs proficient (p)MMR p = 0.0016). Versican proteolysis correlated with increased CD8+ T cell infiltration in dMMR and pMMR cancers and was present in cancers with/without APC, TP53, and KRAS mutations. Across common mutations, cancers with the versican proteolysis predominant phenotype had more CD8+ T-cell infiltration than those without (APC mutant (mt): 11.82 vs 1.97 CD8+ TILs/hpf, p < 0.001; KRAS mt: 9.39 vs 3.08, p = 0.15; BRAF mt: 25.00 vs 7.50, p = 0.13; TP53 mt: 8.61 vs 1.63, p < 0.001). Conclusions: Across common mutations, versican proteolysis predicts CD8+ T-cell infiltration in both dMMR and pMMR CRC. Further investigation into whether this increase in infiltration will lead to greater immunotherapy response is warranted.

scholarly journals The Cationic Antimicrobial Peptide LL-37 Modulates Dendritic Cell Differentiation and Dendritic Cell-Induced T Cell Polarization

2004 ◽  
Vol 172 (4) ◽  
pp. 2704.2-2704 ◽  
Author(s):  
Donald J. Davidson ◽  
Andrew J. Currie ◽  
Gregor S. D. Reid ◽  
Dawn M. E. Bowdish ◽  
Kelly L. MacDonald ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
Dendritic Cell ◽  
Antimicrobial Peptide ◽  
Cell Polarization ◽  
Cationic Antimicrobial Peptide ◽  
Dendritic Cell Differentiation ◽  
T Cell Polarization

Intratumoral T cell infiltration, MHC class I and STAT1 as biomarkers of good prognosis in colorectal cancer

Gut ◽  
2010 ◽  
Vol 59 (7) ◽  
pp. 926-933 ◽  
Author(s):  
J. A. D. Simpson ◽  
A. Al-Attar ◽  
N. F. S. Watson ◽  
J. H. Scholefield ◽  
M. Ilyas ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Mhc Class I ◽  
Good Prognosis ◽  
Class I ◽  
Cell Infiltration ◽  
T Cell Infiltration
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