scholarly journals IMMU-42. CD8+ T-CELLS MEDIATE IMMUNOEDITING, AND INFLUENCE GENOTYPE, TUMOR ONCOGENIC PATHWAYS AND MICROENVIRONMENT DURING PROGRESSION OF MURINE GLIOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi128-vi128
Author(s):  
J Robert Kane ◽  
Junfei Zhao ◽  
Takashi Tsujiuchi ◽  
Brice Laffleur ◽  
Aayushi Mahajan ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Progression ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Mapk Signaling ◽  
Tumor Evolution ◽  
Immune Recognition ◽  
Immune Cell Population ◽  
Immune Effector ◽  
Cancer Immunoediting

Abstract Cancer immunoediting shapes tumor progression by the immunological selection of tumor cell variants that can evade immune recognition. Given the immune evasive cellular diversity of glioblastoma, we hypothesized that CD8+ T-cells mediate immunoediting in this tumor. We evaluated tumor progression in the absence of CD8+ T-cells by depleting this immune cell population in a transgenic murine glioma model. Tumors generated in the absence of CD8+ T-cells developed poorly in recipients with intact immunity, implying a more immunogenic profile. These tumors demonstrated increased chromosomal instability, gene fusions, MAPK signaling, and macrophage infiltration. These observations were stochastic, suggesting variability in the mode of tumor evolution in the absence of this immune effector. MAPK activation was correlated with macrophage recruitment in two transgenic murine models and the human disease. Our results indicate that CD8+ T-cells mediate a strong immunoediting selection in glioblastoma that protect against the hallmarks of cancer and drive immune evasion.

scholarly journals CD8+ T-cell-mediated immunoediting influences genomic evolution and immune evasion in murine gliomas

2019 ◽  
Author(s):  
J. Robert Kane ◽  
Junfei Zhao ◽  
Takashi Tsujiuchi ◽  
Brice Laffleur ◽  
Aayushi Mahajan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cell ◽  
Immune Evasion ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Cd8 T Cell ◽  
Mapk Signaling ◽  
Immune Recognition ◽  
Cancer Immunoediting

AbstractCancer immunoediting shapes tumor progression by the selection of tumor cell variants that can evade immune recognition. Given the immune evasion and intra-tumor heterogeneity intrinsic to gliomas, we hypothesized that CD8+ T-cells mediate immunoediting in these tumors. We evaluated glioma progression in the absence of CD8+ T-cells by depleting this immune cell population in transgenic murine gliomas. Upon transplantation, gliomas that developed in the absence of CD8+ T-cells engrafted poorly in recipients with intact immunity but engrafted well in those with CD8+ T-cell depletion. Gliomas developed in absence of CD8+ T-cells exhibited increased chromosomal instability, MAPK signaling, gene fusions, and macrophage/microglial infiltration. MAPK activation correlated with macrophage/microglial recruitment in this model and in the human disease. Our results indicate that CD8+ T-cells mediate immunoediting during gliomagenesis, influencing the genomic stability of glioma and its microenvironment, leading to immune evasion.SignificanceImmune evasion renders cancer resistant to anti-tumoral immunity. Therapeutic intervention often fails for gliomas because of the plasticity of tumor cell variants that resist immune surveillance. Our results demonstrate a mechanism of immune evasion in gliomas that derives from CD8+ T-cells during the development and progression of this disease.

scholarly journals 602 STING agonist-based treatment promotes vascular normalization and tertiary lymphoid structure formation in the therapeutic melanoma microenvironment

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A637-A637
Author(s):  
Manoj Chelvanambi ◽  
Ronald Fecek ◽  
Jennifer Taylor ◽  
Walter Storkus
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Ex Vivo ◽  
In Vitro Assays ◽  
Type I ◽  
Vascular Normalization ◽  
S 100 ◽  
Transcriptional Changes

BackgroundThe degree of immune infiltration in tumors, especially CD8+ T cells, greatly impacts patient disease course and response to interventional immunotherapy. Hence, enhancement of TIL prevalence is a preferred clinical endpoint, one that may be achieved via administration of agents that normalize the tumor vasculature (VN) leading to improved immune cell recruitment and/or that induce the development of local tertiary lymphoid structures (TLS) within the tumor microenvironment (TME).MethodsLow-dose STING agonist ADU S-100 (5 μg/mouse) was delivered intratumorally to established s.c. B16.F10 melanomas on days 10, 14 and 17 post-tumor inoculation under an IACUC-approved protocol. Treated and control, untreated tumors were isolated at various time points to assess transcriptional changes associated with VN and TLS formation via qPCR, with corollary immune cell composition changes determined using flow cytometry and immunofluorescence microscopy. In vitro assays were performed on CD11c+ BMDCs treated with 2.5 μg/mL ADU S-100 (vs PBS control) and associated transcriptional changes analyzed via qPCR or profiled using DNA microarrays. For TCRβ-CDR3 analyses, CDR3 was sequenced from gDNA isolated from enzymatically digested tumors and splenocytes.ResultsWe report that activation of STING within the TME leads to slowed melanoma growth in association with increased production of angiostatic factors including Tnfsf15 (Vegi), Cxcl10 and Angpt1, and TLS inducing factors including Ccl19, Ccl21, Lta, Ltb and Tnfsf14 (Light). Therapeutic responses from intratumoral STING activation were characterized by increased vascular normalization (VN), enhanced tumor infiltration by CD8+ T cells and CD11c+ DCs and local TLS neo-genesis, all of which were dependent on host expression of STING. Consistent with a central role for DC in TLS formation, ex vivo ADU S-100-activated mCD11c+ DCs also exhibited upregulated expression of TLS promoting factors including lymphotoxin-α (LTA), IL-36, inflammatory chemokines and type I interferons. TLS formation was associated with the development of a therapeutic TIL TCR repertoire enriched in T cell clonotypes uniquely detected within the tumor but not the peripheral circulation in support or local T cell cross-priming within the TME.ConclusionsOur data support the premise that i.t. delivery of STING agonist promotes a pro-inflammatory TME in support of VN and TLS formation, leading to the local expansion of unique TIL repertoire in association with superior anti-melanoma efficacy.

scholarly journals TAMI-07. THE IMMUNE MICROENVIRONMENT IN LOWER GRADE GLIOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii214-ii214
Author(s):  
Anupam Kumar ◽  
Katharine Chen ◽  
Claudia Petritsch ◽  
Theodore Nicolaides ◽  
Mariarita Santi-Vicini ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cd8 T Cells ◽  
Molecular Mechanisms ◽  
T Regulatory Cells ◽  
Immune Cell ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Lower Grade ◽  
Functional Relationships

Abstract The determinants of the tumor-associated immune response in brain tumors are poorly understood. Using tumor samples from two molecularly distinct subtypes of lower grade glioma, MAPK-driven glioma with biallelic inactivation of CDKN2A (n=30) and IDH-mutant, 1p/19q-intact astrocytoma (n=29), we demonstrate qualitative and quantitative differences in the tumor-associated immune response and we investigate the molecular mechanisms involved. Histologically the MAPK-driven gliomas were comprised of pleomorphic xanthoastrocytoma (PXA) (n=11) and anaplastic PXA (n=19). Seven patients had paired samples from two sequential surgeries. Immune cell populations and their activity were determined by quantitative multiplex immunostaining and Digital Spatial Profiling and gene expression was analyzed by Nanostring. Functional studies were performed using established cell lines and two new patient-derived lines from MAPK-driven LGGs. MAPK-driven tumors exhibited an increased number of CD8+ T cells and tumor-associated microglial/macrophage (TAMs), including CD163+ TAMs, as compared to IDH-mutant astrocytoma. In contrast, IDH-mutant tumors had increased FOXP3+ immunosuppressive T regulatory cells. Transcriptional and protein level analyses in MAPK-driven tumors suggested an active cytotoxic T cell response with robust expression of granzyme B, present on 27% of CD8+ T cells, increased MHC class I expression, and altered cytokine profiles. Interestingly, MAPK-driven tumors also had increased expression of immunosuppressive molecules, including CXCR4, PD-L1, and VEGFA. Expression differences for cell surface and secreted proteins were confirmed in patient-derived tumor lines and functional relationships between altered chemokine expression and immune cell infiltration was investigated. Our data provide novel insights into the immune contexture of MAPK driven LGGs and suggest MAPK driven gliomas with biallelic inactivation of CDKN2A may be particularly vulnerable to immunotherapeutic modulation

scholarly journals Tumor morphology and location associate with immune cell composition in pleomorphic sarcoma

2021 ◽  
Author(s):  
Rosanna L. Wustrack ◽  
Evans Shao ◽  
Joey Sheridan ◽  
Melissa Zimel ◽  
Soo-Jin Cho ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Cd8 T Cells ◽  
Tumor Size ◽  
Immune Cell ◽  
Human Cancer ◽  
Soft Tissue Sarcomas ◽  
Inverse Correlation ◽  
Anatomical Location ◽  
Pleomorphic Sarcoma

Abstract Background Soft-tissue sarcomas (STS) are a rare group of mesenchymal malignancies that account for approximately 1% of adult human cancer. Undifferentiated pleomorphic sarcoma (UPS) is one of the most common subtypes of adult STS. Clinical stratification of UPS patients has not evolved for decades and continues to rely on tumor-centric metrics including tumor size and depth. Our understanding of how the tumor microenvironment correlates to these clinicopathologic parameters remains limited. Methods Here, we performed single-cell flow cytometric immune-based profiling of 15 freshly resected UPS tumors and integrated this analysis with clinical, histopathologic, and outcomes data using both a prospective and retrospective cohort of UPS patients. Results We uncovered a correlation between physiologic and anatomic properties of UPS tumors and the composition of immune cells in the tumor microenvironment. Specifically, we identified an inverse correlation between tumor-infiltrating CD8 + T cells and UPS tumor size; and a positive correlation between tumor-infiltrating CD8 + T cells and overall survival. Moreover, we demonstrate an association between anatomical location (deep or superficial) and frequency of CD4 + PD1hi infiltrating T cells in UPS tumors. Conclusions Our study provides an immune-based analysis of the tumor microenvironment in UPS patients and describes the different composition of tumor infiltrating lymphocytes based on size and tumor depth.

scholarly journals Immune classification of clear cell renal cell carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sumeyye Su ◽  
Shaya Akbarinejad ◽  
Leili Shahriyari
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Renal Cell ◽  
Cd4 T Cells ◽  
Immune Cell ◽  
Clear Cell ◽  
P Value ◽  
Cell Type ◽  
Primary Tumors ◽  
Immune Cell Type

AbstractSince the outcome of treatments, particularly immunotherapeutic interventions, depends on the tumor immune micro-environment (TIM), several experimental and computational tools such as flow cytometry, immunohistochemistry, and digital cytometry have been developed and utilized to classify TIM variations. In this project, we identify immune pattern of clear cell renal cell carcinomas (ccRCC) by estimating the percentage of each immune cell type in 526 renal tumors using the new powerful technique of digital cytometry. The results, which are in agreement with the results of a large-scale mass cytometry analysis, show that the most frequent immune cell types in ccRCC tumors are CD8+ T-cells, macrophages, and CD4+ T-cells. Saliently, unsupervised clustering of ccRCC primary tumors based on their relative number of immune cells indicates the existence of four distinct groups of ccRCC tumors. Tumors in the first group consist of approximately the same numbers of macrophages and CD8+ T-cells and and a slightly smaller number of CD4+ T cells than CD8+ T cells, while tumors in the second group have a significantly high number of macrophages compared to any other immune cell type (P-value $$<0.01$$ < 0.01 ). The third group of ccRCC tumors have a significantly higher number of CD8+ T-cells than any other immune cell type (P-value $$<0.01$$ < 0.01 ), while tumors in the group 4 have approximately the same numbers of macrophages and CD4+ T-cells and a significantly smaller number of CD8+ T-cells than CD4+ T-cells (P-value $$<0.01$$ < 0.01 ). Moreover, there is a high positive correlation between the expression levels of IFNG and PDCD1 and the percentage of CD8+ T-cells, and higher stage and grade of tumors have a substantially higher percentage of CD8+ T-cells. Furthermore, the primary tumors of patients, who are tumor free at the last time of follow up, have a significantly higher percentage of mast cells (P-value $$<0.01$$ < 0.01 ) compared to the patients with tumors for all groups of tumors except group 3.

scholarly journals Peripheral Levels of EPCs, T Cells, and Macrophages’ as Possible Predictive Biomarkers of Acute Myocardial Infarction

2020 ◽  
Author(s):  
Amankeldi Salybekov ◽  
Katsuaki Sakai ◽  
Makoto Natsumeda ◽  
Kosit Vorateera ◽  
Shuzo Kobayashi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
T Cells ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Temporal Dynamics ◽  
Predictive Biomarkers ◽  
Mortality And Morbidity ◽  
Patients With Diabetes ◽  
Functionally Impaired

Abstract Acute myocardial infarction (AMI), with a very relevant global disease burden, remains the major mortality and morbidity cause among all cardiovascular diseases. Patient prognosis is strictly dependent on early diagnosis and the adoption of adequate interventions. AMI diagnosis requires constant optimization, particularly considering the individuals at higher risk (or more vulnerable to worse outcomes) such as patients with diabetes mellitus and atherosclerosis. Herein, we investigated the levels of peripheral blood EPCs and immune cell-subsets from myeloid and lymphoid lineages, as well as their temporal dynamics, in the quest for new prognostic biomarkers of AMI. We collected blood from 18 hospitalized patients (days 3 and 7 after AMI onset) and 16 healthy volunteers, and resolved their circulating PBMC populations via flow cytometry. Overall, our data demonstrate a significant decrease in peripheral EPCs and CD8+ T cells, three days following an AMI. EPCs appear to be functionally impaired in AMI patients, and their circulating numbers associate with cardiac vessel lesions. Furthermore, CD8+ T cells (and even M1-macrophages) in the periphery, in combination with the classical laboratory determinations, may serve as high accuracy biomarkers of AMI, potentially aiding to prevent worse AMI outcomes.

Tumor progression inhibits the induction of multifunctionality in adoptively transferred tumor-specific CD8+ T cells

2008 ◽  
Vol 39 (1) ◽  
pp. 241-253 ◽  
Author(s):  
Naoko Imai ◽  
Hiroaki Ikeda ◽  
Isao Tawara ◽  
Hiroshi Shiku
Keyword(s):  
T Cells ◽  
Tumor Progression ◽  
Cd8 T Cells
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