Mismatch repair deficiency in cholangiocarcinoma.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 269-269 ◽  
Author(s):  
Paul Raymond Kunk ◽  
Joseph Mounir Obeid ◽  
Kevin Winters ◽  
Patcharin Pramoonjago ◽  
Dirk G. Brockstedt ◽  
...  
Keyword(s):  
T Cell ◽  
Mismatch Repair ◽  
Immune Cell ◽  
Tissue Microarrays ◽  
High Rate ◽  
Cell Infiltration ◽  
T Cell Infiltration ◽  
Mmr Deficiency ◽  
Unmet Treatment Need ◽  
Mesothelin Expression

269 Background: Cholangiocarcinoma (CC) is a fatal malignancy with an unmet treatment need. With the approval of immunotherapy for solid tumors with mismatch repair (MMR) deficiency, there is a renewed interest in MMR testing. Little is known about the incidence of MMR deficiency in CC or its correlation to survival, immune cell infiltration, PD-L1 and other proteins expressed in CC such as mesothelin. Methods: CC tumors were identified from patients treated at the University of Virginia from 2000-2014. Tissue microarrays (TMAs) were constructed of 3-4 cores from each tumor and were stained by immunohistochemistry for MMR genes (MLH1, PMS2, MSH2, MSH6), mesothelin, PD-L1 and immune cells. TMAs were scanned using the Leica SCN400 and analyzed using the Digital Image Hub software. Stain intensity thresholds for defining positive cells were determined by two users and recorded as an average of all cores from each tumor. Mesothelin and PD-L1 expression were measured as a percentage of positive tumor cells. Correlation with overall survival was assessed using log-rank tests and classification and regression trees, with p values < 0.05 considered significant. Results: Ninety-one tumors were analyzed: 24 intrahepatic, 33 hilar, and 34 distal. MMR deficiency was found in 20 tumors (22%). None of the MMR deficient tumors co-expressed PD-L1 (>1%), which was found in 15% of the remaining tumors. T cell infiltration (CD4, CD8 and FoxP3) did not differ between MMR deficient or proficient tumors. Patients with MMR deficiency had a trend towards worse survival compared to those with proficiency (median OS: 19.2 vs. 28.1 months, p = 0.07). MMR deficient tumors showed a lower mesothelin expression compared to MMR proficient tumors, median 8 vs. 129 positive cells per TMA (p = 0.08). Patients with MMR deficiency and low mesothelin expression had a worse outcome compared to patients with MMR proficiency and high mesothelin expression (median OS: 14.5 vs. 30.0 months, p = 0.05). Conclusions: Given the high rate of MMR deficiency, all CC tumors should be tested and may benefit from anti-PD-1 therapy. The poor prognosis of MMR deficient CC may be independent of T-cell infiltration and additional studies are needed to better characterize the genetic and molecular landscape of this subset of tumors.

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

2020 ◽  
Vol 9 (6) ◽  
pp. 1741 ◽  
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.

scholarly journals Updates on Immunotherapy and Immune Landscape in Renal Clear Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5856
Author(s):  
Myung-Chul Kim ◽  
Zeng Jin ◽  
Ryan Kolb ◽  
Nicholas Borcherding ◽  
Jonathan Alexander Chatzkel ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Single Cell Analysis ◽  
Clear Cell ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Cellular Mechanisms ◽  
T Cell Infiltration ◽  
Immunological Mechanisms

Several clinicopathological features of clear cell renal cell carcinomas (ccRCC) contribute to make an “atypical” cancer, including resistance to chemotherapy, sensitivity to anti-angiogenesis therapy and ICIs despite a low mutational burden, and CD8+ T cell infiltration being the predictor for poor prognosis–normally CD8+ T cell infiltration is a good prognostic factor in cancer patients. These “atypical” features have brought researchers to investigate the molecular and immunological mechanisms that lead to the increased T cell infiltrates despite relatively low molecular burdens, as well as to decipher the immune landscape that leads to better response to ICIs. In the present study, we summarize the past and ongoing pivotal clinical trials of immunotherapies for ccRCC, emphasizing the potential molecular and cellular mechanisms that lead to the success or failure of ICI therapy. Single-cell analysis of ccRCC has provided a more thorough and detailed understanding of the tumor immune microenvironment and has facilitated the discovery of molecular biomarkers from the tumor-infiltrating immune cells. We herein will focus on the discussion of some major immune cells, including T cells and tumor-associated macrophages (TAM) in ccRCC. We will further provide some perspectives of using molecular and cellular biomarkers derived from these immune cell types to potentially improve the response rate to ICIs in ccRCC patients.

scholarly journals Single cell transcriptomics reveals the effect of PD-L1/TGF-β blockade on the tumor microenvironment

2020 ◽  
Author(s):  
Yoong Wearn Lim ◽  
Garry L. Coles ◽  
Savreet K. Sandhu ◽  
David S. Johnson ◽  
Adam S. Adler ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
Immune Cell ◽  
Single Cells ◽  
Cell Infiltration ◽  
Cytotoxic Lymphocytes ◽  
T Cell Infiltration ◽  
Anti Tumor Activity

AbstractBackgroundThe anti-tumor activity of anti-PD-1/PD-L1 therapies correlates with T cell infiltration in tumors. Thus, a major goal in oncology is to find strategies that enhance T cell infiltration and efficacy of anti-PD-1/PD-L1 therapy. TGF-β has been shown to contribute to T cell exclusion and anti-TGF-β improves anti-PD-L1 efficacy in vivo. However, TGF-β inhibition has frequently been shown to induce toxicity in the clinic, and the clinical efficacy of combination PD-L1 and TGF-β blockade has not yet been proven. To identify strategies to overcome resistance to PD-L1 blockade, the transcriptional programs associated with PD-L1 and/or TGF-β blockade in the tumor microenvironment should be further elucidated.ResultsFor the first time, we used single-cell RNA sequencing to characterize the transcriptomic effects of PD-L1 and/or TGF-β blockade on nearly 30,000 single cells in the tumor and surrounding microenvironment. Combination treatment led to upregulation of immune response genes, including multiple chemokine genes such as CCL5, in CD45+ cells, and down-regulation of extracellular matrix genes in CD45-cells. Analysis of publicly available tumor transcriptome profiles showed that the chemokine CCL5 was strongly associated with immune cell infiltration in various human cancers. Further investigation with in vivo models showed that intratumorally administered CCL5 enhanced cytotoxic lymphocytes and the anti-tumor activity of anti-PD-L1.ConclusionsTaken together, our data could be leveraged translationally to improve anti-PD-L1 plus anti-TGF-β combination therapy, for example through companion biomarkers, and/or to identify novel targets that could be modulated to overcome resistance.

scholarly journals Improved Immunotherapy Efficacy by Vascular Modulation

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5207
Author(s):  
Emma L. Newport ◽  
Ana Rita Pedrosa ◽  
Alexandra Njegic ◽  
Kairbaan M. Hodivala-Dilke ◽  
José M. Muñoz-Félix
Keyword(s):  
T Cell ◽  
Cancer Therapy ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Cell Infiltration ◽  
Cell Therapies ◽  
T Cell Infiltration ◽  
Tumour Oxygenation

Several strategies have been developed to modulate the tumour vasculature for cancer therapy including anti-angiogenesis and vascular normalisation. Vasculature modulation results in changes to the tumour microenvironment including oxygenation and immune cell infiltration, therefore lending itself to combination with cancer therapy. The development of immunotherapies has led to significant improvements in cancer treatment. Particularly promising are immune checkpoint blockade and CAR T cell therapies, which use antibodies against negative regulators of T cell activation and T cells reprogrammed to better target tumour antigens, respectively. However, while immunotherapy is successful in some patients, including those with advanced or metastatic cancers, only a subset of patients respond. Therefore, better predictors of patient response and methods to overcome resistance warrant investigation. Poor, or periphery-limited, T cell infiltration in the tumour is associated with poor responses to immunotherapy. Given that (1) lymphocyte recruitment requires leucocyte–endothelial cell adhesion and (2) the vasculature controls tumour oxygenation and plays a pivotal role in T cell infiltration and activation, vessel targeting strategies including anti-angiogenesis and vascular normalisation in combination with immunotherapy are providing possible new strategies to enhance therapy. Here, we review the progress of vessel modulation in enhancing immunotherapy efficacy.

scholarly journals DNA Methylation based glioblastoma subclassification is related to tumoral T cell infiltration and patient survival

2020 ◽  
Author(s):  
Joost Dejaegher ◽  
Lien Solie ◽  
Zoé Hunin ◽  
Raf Sciot ◽  
David Capper ◽  
...  
Keyword(s):  
Dna Methylation ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Methylation Pattern ◽  
Response To Therapy ◽  
Cell Infiltration ◽  
Mesenchymal Tumors ◽  
T Cell Infiltration

Abstract Background Histologically classified Glioblastomas (GBM) can have different clinical behavior and response to therapy, for which molecular subclassifications have been proposed. We evaluated the relationship of epigenetic GBM subgroups with immune cell infiltrations, systemic immune changes during radiochemotherapy and clinical outcome. Methods 450K genome-wide DNA methylation was assessed on tumor tissue from 93 patients with newly diagnosed GBM, treated with standard radiochemotherapy and experimental immunotherapy. Tumor infiltration of T cells, myeloid cells and PD-1 expression were evaluated. Circulating immune cell populations and selected cytokines were assessed on blood samples taken before and after radiochemotherapy. Results Forty-two tumors had a mesenchymal, 27 a RTK II, 17 a RTK I and 7 an IDH DNA methylation pattern Mesenchymal tumors had the highest amount of tumor-infiltrating CD3+ and CD8+ T cells and IDH tumors the lowest. There were no significant differences for CD68+ cells, FoxP3+ cells and PD-1 expression between groups. Systemically, there was a relative increase of CD8+ T cells and CD8+ PD-1 expression and a relative decrease of CD4+ T cells after radiochemotherapy in all subgroups except IDH tumors. Overall survival was the longest in the IDH group (median 36 months), intermediate in RTK II tumors (27 months) and significantly lower in mesenchymal and RTK I groups (15.5 and 16 months respectively). Conclusions Methylation based stratification of GBM is related to T cell infiltration and survival, with IDH and mesenchymal tumors representing both ends of a spectrum. DNA methylation profiles could be useful in stratifying patients for immunotherapy trials.

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.

Tumor-derived GDF-15 to suppress t-lymphocyte recruitment to the tumor microenvironment resulting in resistance to ANTI-PD-1 treatment.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14532-e14532
Author(s):  
Joerg Wischhusen ◽  
Markus Haake ◽  
Neha Vashist ◽  
Sabrina Genßler ◽  
Kilian Wistuba-Hamprecht ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cell ◽  
Serum Levels ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
T Cell Infiltration ◽  
Melanoma Patients

e14532 Background: Growth and differentiation factor 15 (GDF-15) is a divergent member of the TGF-β superfamily with low to absent expression in healthy tissue. GDF-15 has been linked to feto-maternal immune tolerance, to prevention of excessive immune cell infiltration during tissue damage, and to anorexia. Various major tumor types secrete high levels of GDF-15. In cancer patients, elevated GDF-15 serum levels correlate with poor prognosis and reduced overall survival (OS). Methods: Impact of a proprietary GDF-15 neutralizing antibody (CTL-002) regarding T cell trafficking was analyzed by whole blood adhesion assays, a HV18-MK melanoma-bearing humanized mouse model and a GDF-15-transgenic MC38 model. Additionally, patient GDF-15 serum levels were correlated with clinical response and overall survival in oropharyngeal squamous cell carcinoma (OPSCC) and melanoma brain metastases. Results: In whole blood cell adhesion assays GDF-15 impairs adhesion of T and NK cells to activated endothelial cells. Neutralization of GDF-15 by CTL-002 rescued T cell adhesion. In HV18-MK-bearing humanized mice CTL-002 induced a strong increase in TIL numbers. Subset analysis revealed an overproportional enrichment of T cells, in particular CD8+ T cells. As immune cell exclusion is detrimental for checkpoint inhibitor (CPI) therapy, a GDF-15-transgenic MC38 model was tested for anti-PD-1 therapy efficacy. In GDF-15 overexpressing MC38 tumors response to anti PD-1 therapy was reduced by 90% compared to wtMC38 tumors. Combining aPD-1 with CTL-002 resulted in 50% of the mice rejecting their GDF-15 overexpressing tumors. Clinically, inverse correlations of GDF-15 levels with CD8+ T cell infiltration were shown for HPV+ OPSCC and for melanoma brain metastases. GDF-15 serum levels were significantly higher in HPV- than in HPV+ OPSCC patient (p < 0.0001). Low GDF-15 levels corresponded to longer OS in both HPV- and HPV+ OPSCC. In two independent melanoma patient cohorts treated with nivolumab or pembrolizumab low baseline serum GDF-15 levels were predictive for clinical response to anti-PD1 treatment and superior OS. Bivariate analysis including LDH indicates that GDF-15 independently predicts poor survival in aPD-1 treated melanoma patients. Conclusions: Taken together our in vitro and in vivo data show that elevated GDF-15 levels block T-cell infiltration into tumor tissues. Neutralizing GDF-15 with CTL-002 restores the ability of T cells to extravasate blood vessels and enter tumor tissue both in vitro and in vivo. In melanoma, patients with higher GDF-15 levels have significantly shorter survival and are less likely to respond to anti-PD1 therapy. GDF-15 may thus serve as a new predictive biomarker for anti-PD1 response, but most importantly also represents a novel target for cancer immunotherapy to improve tumor immune cell infiltration and response to anti-PD1 therapy.

Abstract WP142: Targeting VCAM1 to Reduce Acute and Chronic Neuroinflammation After Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Kristy Zera ◽  
Todd Peterson ◽  
Hanadie Youdef ◽  
Davis Lee ◽  
Tony Wyss-Coray ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocyte ◽  
Immune Cell ◽  
Artery Occlusion ◽  
Cell Infiltration ◽  
Lymphocyte Infiltration ◽  
Ischemic Lesion ◽  
Post Stroke ◽  
T Cell Infiltration ◽  
Chronic Neuroinflammation

Background: Ischemia-induced neuroinflammmation is associated with worse outcomes after stroke. The innate immune response can mediate infarct expansion and impair short-term recovery, while adaptive responses lead to chronic neuroinflammation, neurodegeneration remote to the ischemic lesion, and consequent vascular dementia. Vascular cell adhesion molecule 1 (VCAM1) is an endothelial protein that facilitates vascular-immune cell interactions by binding very late antigen-4 (VLA-4). Soluble VCAM1 plasma levels are elevated in stroke patients and in aging people and mice. In aging mice, blocking VCAM1 ameliorates age-induced neuroinflammation and cognitive impairment. Objective: To determine if acute anti-VCAM1 treatment in mice would reduce microgliosis and astrogliosis, while delayed treatment would reduce B and T lymphocyte infiltration. Methodology: Adult (3-month-old) C57BL/6 mice (N=10/group) underwent permanent distal middle cerebral artery occlusion and were dosed with anti-VCAM1 antibody 4h post-stroke, then sacrificed at 72h. Microgliosis and astrogliosis were quantified as percent area immunostained in the infarct border by Iba1 and GFAP, respectively. Results: Acute treatment reduced microgliosis by 30% (p=0.0476) and astrogliosis 39% (p<0.03). Additionally, adult mice (N=10/group) were treated with anti-VCAM1 immediately (4h) or later (4d) post-stroke and euthanized 3 weeks later. B cell infiltration was quantified as percent stroke core immunostained by B220, while T lymphocyte infiltration was quantified as CD3+ cells in the core. Delayed anti-VCAM1 significantly reduced B and T cell infiltration by approximately 25% (p=0.0015) and 50% (p=0.0192), respectively. In contrast, early anti-VCAM1 had no effect on B/T cell infiltration. Conclusions: Together, these findings establish VCAM1 as a possible therapeutic target to prevent stroke-induced neuroinflammation in both acute and chronic settings.

scholarly journals Higher cytolytic score correlates with an immunosuppressive tumor microenvironment and reduced survival in glioblastoma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Alexander F. Haddad ◽  
Jia-Shu Chen ◽  
Taemin Oh ◽  
Matheus P. Pereira ◽  
Rushikesh S. Joshi ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Cell ◽  
Cell Types ◽  
Cd8 T Cell ◽  
The Cancer Genome Atlas ◽  
Cell Infiltration ◽  
Sequencing Data ◽  
Gene Score ◽  
T Cell Infiltration ◽  
The Relationship

Abstract Cytolytic score (CYT), calculated from mRNA expression levels of granzyme and perforin, positively correlates with CD8+ T cell infiltration/activity in a variety of cancers. Unlike other cancers, higher CYT has been associated with worse prognosis in glioblastoma (GBM). To address this discrepancy, we sought to investigate the relationship between CYT and immune checkpoint gene score (ICGscore), as well as their correlation with patient survival and tumor immune cell infiltration. Clinical and RNA-sequencing data for patients with newly diagnosed GBM were obtained from The Cancer Genome Atlas. Maximally-selected rank statistics was used to dichotomize subgroups. CIBERSORT was used to estimate abudence of immune cell-types. Spearman correlation was used to characterize the relationship between CYT and ICGscore. Kaplan–Meier curves were generated for survival analysis. Overall, 28/151 patients had high CYT. High CYT was associated with a mesenchymal subtype (p < 0.001) and worse survival (7.45 vs. 12.2 months, p < 0.001). There were no differences in patient demographics, IDH/MGMT mutation status, or treatment. On subgroup analysis, patients with high CYT/ICGscore had significantly increased CD8+ infiltration (p < 0.001), as expected, and worse survival (HR 0.445, p < 0.01). Furthermore, CYT strongly correlated with ICGscore (RS = 0.675, p < 0.001). The high CYT/ICGscore subgroup was associated with greater infiltration of M2 macrophages (p = 0.011) and neutrophils (p = 0.055). Our study highlights a multidimensional immunosuppressive GBM microenvironment in patients with higher CYT and potentially identifies patients with high CYT/ICGscore as a subgroup that may particularly benefit from multi-faceted immunotherapies, given their already elevated tumor CD8+ T cell levels.

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