Abstract A085: Immune evasion and PD-1-positive T cell infiltration in DNA mismatch repair-deficient colorectal cancer

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.

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Implications of Hereditary Origin on the Immune Phenotype of Mismatch Repair-Deficient Cancers: Systematic Literature Review

Journal of Clinical Medicine ◽

10.3390/jcm9061741 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1741 ◽

Cited By ~ 2

Author(s):

Lena Bohaumilitzky ◽

Magnus von Knebel Doeberitz ◽

Matthias Kloor ◽

Aysel Ahadova

Keyword(s):

T Cell ◽

Immune Responses ◽

Mismatch Repair ◽

Science Studies ◽

Immune Checkpoint Blockade ◽

Cell Infiltration ◽

Dna Mismatch ◽

T Cell Infiltration ◽

Hereditary Tumors ◽

Mmr Deficiency

Microsatellite instability (MSI) represents one of the major types of genomic instability in human cancers and is most common in colorectal cancer (CRC) and endometrial cancer (EC). MSI develops as a consequence of DNA mismatch repair (MMR) deficiency, which can occur sporadically or in the context of Lynch syndrome (LS), the most common inherited tumor syndrome. MMR deficiency triggers the accumulation of high numbers of somatic mutations in the affected cells, mostly indel mutations at microsatellite sequences. MSI tumors are among the most immunogenic human tumors and are often characterized by pronounced local immune responses. However, so far, little is known about immunological differences between sporadic and hereditary MSI tumors. Therefore, a systematic literature search was conducted to comprehensively collect data on the differences in local T cell infiltration and immune evasion mechanisms between sporadic and LS-associated MSI tumors. The vast majority of collected studies were focusing on CRC and EC. Generally, more pronounced T cell infiltration and a higher frequency of B2M mutations were reported for LS-associated compared to sporadic MSI tumors. In addition, phenotypic features associated with enhanced lymphocyte recruitment were reported to be specifically associated with hereditary MSI CRCs. The quantitative and qualitative differences clearly indicate a distinct biology of sporadic and hereditary MSI tumors. Clinically, these findings underline the need for differentiating sporadic and hereditary tumors in basic science studies and clinical trials, including trials evaluating immune checkpoint blockade therapy in MSI tumors.

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

Science Translational Medicine ◽

10.1126/scitranslmed.abf0992 ◽

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

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Mismatch repair deficiency is not sufficient to elicit tumor immunogenicity

10.21203/rs.3.rs-879464/v1 ◽

2021 ◽

Author(s):

Tyler Jacks ◽

Peter Westcott ◽

Francesc Muyas ◽

Olivia Smith ◽

Haley Hauck ◽

...

Keyword(s):

T Cell ◽

Mismatch Repair ◽

Immune Checkpoint Blockade ◽

Cell Infiltration ◽

Mismatch Repair Deficiency ◽

Dna Mismatch ◽

T Cell Infiltration ◽

Repair Deficiency ◽

Tumor Mutational Burden

Abstract DNA mismatch repair deficiency (MMRd) is associated with high tumor mutational burden (TMB), increased T cell infiltration, and remarkable responsiveness to immune checkpoint blockade (ICB) therapy1. Nevertheless, about half of MMRd tumors do not respond to ICB for unclear reasons. While cell line transplant models of MMRd have reinforced the importance of TMB in immune response2,3, critical questions remain regarding the role of immunosurveillance in the evolution of MMRd tumors induced in vivo. Here, we developed autochthonous mouse models of lung and colon cancer with ablation of MMR via in vivo CRISPR/Cas9 targeting. Surprisingly, MMRd in these models did not increase T cell infiltration or response to ICB. Mechanistically, we showed this lack of immunogenicity to be driven by profound intratumoral heterogeneity. Studies in immune deficient animals further demonstrated that immunosurveillance in MMRd tumors has no impact on TMB but shapes the clonal architecture of neoantigens by exacerbating heterogeneity. These results provide important context for understanding immune evasion in cancers with high TMB and have major implications for therapies aimed at increasing TMB.

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DNA Mismatch Repair Status Predicts Need for Future Colorectal Surgery for Metachronous Neoplasms in Young Individuals Undergoing Colorectal Cancer Resection

Diseases of the Colon & Rectum ◽

10.1097/dcr.0000000000000391 ◽

2015 ◽

Vol 58 (7) ◽

pp. 645-652 ◽

Cited By ~ 14

Author(s):

Melyssa Aronson ◽

Spring Holter ◽

Kara Semotiuk ◽

Laura Winter ◽

Aaron Pollett ◽

...

Keyword(s):

Colorectal Cancer ◽

Colorectal Surgery ◽

Mismatch Repair ◽

Dna Mismatch Repair ◽

Cancer Resection ◽

Metachronous Neoplasms ◽

Dna Mismatch ◽

Colorectal Cancer Resection ◽

Mismatch Repair Status

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Potential Germline Epimutations in Lynch Syndrome: More Evidence for Genetics Superseding Epigenetics in Inactivation of DNA Mismatch Repair Genes in Hereditary Colorectal Cancer

Gastroenterology ◽

10.1053/j.gastro.2009.08.020 ◽

2009 ◽

Vol 137 (4) ◽

pp. 1524-1527

Author(s):

Matthias P.A. Ebert ◽

Oliver G. Opitz

Keyword(s):

Colorectal Cancer ◽

Lynch Syndrome ◽

Mismatch Repair ◽

Dna Mismatch Repair ◽

Hereditary Colorectal Cancer ◽

Mismatch Repair Genes ◽

Dna Mismatch ◽

Dna Mismatch Repair Genes ◽

Repair Genes

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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

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.342 ◽

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).

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