TRIB3 reduces CD8 + T cell infiltration and induces immune evasion by repressing the STAT1-CXCL10 axis in colorectal cancer

2022 ◽  
Vol 14 (626) ◽  
Author(s):  
Shuang Shang ◽  
Yu-wei Yang ◽  
Fei Chen ◽  
Liang Yu ◽  
Shuo-hao Shen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Immune Evasion ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
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

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.

Versican proteolysis as a key regulator of CD8+ T-cell infiltration in colorectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15082-e15082
Author(s):  
Dustin A. Deming ◽  
Chelsea Hope ◽  
Philip Emmerich ◽  
Adam Pagenkopf ◽  
Kristina Matkowskyj ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Mismatch Repair ◽  
Tumor Infiltrating Lymphocytes ◽  
Cd8 T Cell ◽  
Staining Intensity ◽  
Cell Infiltration ◽  
Tissue Samples ◽  
Tumor Bed ◽  
T Cell Infiltration

e15082 Background: Colorectal cancer (CRC) originates within immunologically complex microenvironments. To date the benefits of immunotherapy have been modest except in neoantigen-laden mismatch repair (MMR)-deficient tumors. Approaches to enhance tumor-infiltrating lymphocytes (TILS) in the tumor bed may substantially augment clinical immunotherapy responses. Proteolysis of the tolerogenic matrix proteoglycan versican (VCAN) generates a bioactive fragment, versikine, with putative immunostimulatory activities. Methods: Matched normal and CRC tissue samples were collected from 122 patients with cancers across all stages and locations throughout the colon and rectum. These samples were stained for VCAN, αDPEAAE (neoepitope generated in cleaving VCAN to versikine), and CD8 and scored by a pathologist. Tumors were classified as VCAN proteolysis-predominant (VPP) if their staining for total VCAN staining intensity was < 1+ and staining for VCAN proteolysis (αDPEAAE antibody) was > 2. Conversely, tumors were classified as VCAN proteolysis-weak (VPW) if intact VCAN staining intensity was > 1+ or αDPEAAE intensity was < 2+. IHC for mismatch repair (MMR) proteins was also performed. Results: Overall increased VCAN staining was observed in cancer versus (vs) normal tissue. VPP tumors had a 10 fold greater infiltration of CD8+ T-cells vs VPW cancers (p < 0.001). The correlation between VCAN proteolysis and CD8+ T-cell infiltration was maintained in both cancers with proficient (p) MMR and deficient (d) MMR. In both pMMR and dMMR, the VPP tumors had the greatest degree of CD8+ T-cell infiltration (Wilcoxon rank sum tests: pMMR p = 0.006; dMMR p = 0.03). Among the VPP tumors there was a greater degree of CD8+ T cell infiltration in the dMMR cancers vs pMMR cancers (35 versus 14.8 TILs per high power filed, p = 0.04). Nuclear CTNNB1, a marker for activation of WNT signaling, negatively correlated with CD8+ T cell infiltration( p = 0.014). In addition, VCAN accumulation correlated with the presence of nuclear CTNNB1 (p < 0.001) Conclusions: This is the first description indicating that VCAN proteolysis may shape CRC immune contexture and provide a rationale for testing VCAN proteolysis as a predictive and/or prognostic immune biomarker.

scholarly journals 404 Initial biomarker and clinical data of a phase 2a study of NT-I7, a long-acting interleukin-7, plus pembrolizumab: cohort of subjects with checkpoint inhibitor-naïve advanced MSS-colorectal cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A435-A435
Author(s):  
Richard Kim ◽  
Minal Barve ◽  
Hirva Mamdani ◽  
Melissa Johnson ◽  
Byung Ha Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Checkpoint Inhibitor ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Long Acting ◽  
Anti Tumor Activity

BackgroundCheckpoint inhibitor (CPI) monotherapy is ineffective for microsatellite stable colorectal cancer (MSS-CRC). NT-I7 (efineptakin alfa) is the first-in-class long-acting IL-7 that can increase T-cell infiltration in the tumor microenvironment (TME). We hypothesize that NT-I7 may create a favorable immune-reactive TME to enhance the efficacy of CPI when combined with pembrolizumab (pembro).MethodsThis is an open-label, phase 2a study in subjects with relapsed/refractory (R/R) tumors, including CPI-naïve R/R MSS-CRC. Subjects received the recommended-phase-2-dose of NT-I7 intramuscularly at 1200 µg/kg every 6 weeks (Q6W) plus pembro 200 mg intravenously Q3W. Preliminary anti-tumor activity based on Overall Response Rate (ORR) was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as a primary objective and by iRECIST as an exploratory objective. Biomarker analyses in peripheral blood and tumor biopsies were performed.ResultsAs of 15-July-2021, 19 subjects were enrolled in the CPI-naïve R/R MSS-CRC cohort. Six subjects are ongoing. Median age 58 years [37–81], ECOG PS 0 (26%), 1 (74%). Sixteen (84%) subjects received ≥ 2 prior therapies. All subjects had metastatic or locally advanced disease at enrollment. The median duration of follow-up was 4.64 months. Among 15 evaluable subjects, disease-control rate (DCR) based on RECIST1.1 was 47% and 1 subject achieved partial response per iRECIST (iPR) with 33% tumor reduction. Treatment-related adverse events (AEs) occurred in 14 (73.7%) subjects, 9 (47.4%) G1–2 events and 5 (26.3%) G3 events; no G4 or G5 AEs were reported. No subjects discontinued from the study due to AE. NT-I7 + pembro elicited a significant increase in the absolute lymphocyte count that peaked at week 3 (>3X from baseline, p<0.0001) and was sustained at least until week 18. CD4+/CD8+ T-cell subsets followed the same response pattern. Importantly, Stem-Cell Memory CD8+ T-cells (TSCM), the potential target for CPIs that differentiate into effectors, were remarkably increased post-study treatment (>25X from baseline, p<0.01). Plasmatic chemokines (CXCL9, CXCL10, CXCL11 and CCL9) were significantly increased after the first dose. The iPR subject had an enhanced T-cell infiltration in the TME at week 5. Subject’s follow-up continues and more updated data will be presented.ConclusionsThe chemo-free combination of NT-I7 + pembro was well tolerated and showed encouraging anti-tumor activity in subjects with CPI-naïve R/R MSS-CRC. Increased TSCM and CD8+ T-cell infiltration in TME may be the underlying mechanisms of action for the observed efficacy. These results support continued evaluation of NT-I7 + pembro in CPI-naïve subjects with R/R MSS-CRC.AcknowledgementsThe authors thank ICON for their partnership in conducting this trial.Trial RegistrationNCT04332653Ethics ApprovalThe trial was approved by MD Anderson IRB (#2020–0008_MOD001), Mary Crowley IRB (#20–13) and Advarra IRB (#Pro00042639)All participant gave informed consent prior to study enrollment.

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