ARID1A mutation to define an immunologically active subgroup in patients with microsatellite-stable colorectal cancer.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 215-215
Author(s):  
Amir Mehrvarz Sarshekeh ◽  
Jason Roszik ◽  
Ganiraju C. Manyam ◽  
Shailesh M. Advani ◽  
Jason Willis ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Immune Checkpoint ◽  
Cell Function ◽  
Immune Therapy ◽  
Silent Mutation ◽  
Cytotoxic T Cell ◽  
Wild Type ◽  
Frame Shift ◽  
Ifn Γ

215 Background: AT-rich interactive domain 1A (ARID1A) is a chromatin regulator mutated in human cancers, frequently resulting in truncation and loss of expression of this protein. ARID1A recruits MSH2 during DNA replication to perform mismatch-repair. ARID1A deficiency has been shown to increase mutational load and immune activation in preclinical models (Shen J, Nat Med 2018) but its role in colorectal cancer (CRC) patients (pts) is being explored. Methods: The DNA sequencing and gene expression profiling of microsatellite-stable (MSS) CRC pts were extracted from TCGA and MD Anderson Cancer Center databases. The expression levels were normalized according to the mean values of each dataset. The mutational burden and expression signatures for IFN-γ and various immune markers were compared according to the ARID1A mutational status. Results: Among 417 pts with MSS CRC, 28 pts (6.7%) had a non-silent mutation in ARID1A. Out of the 58 genes most commonly mutated in CRC, non-silent mutation in ARID1A had the strongest association with the frame-shift mutation rate in MSS cases (8-fold increase, p< .001). ARID1A mutation had also a strong correlation with the IFN-γ expression signature in MSS CRC (Δz score +1.91, p< .001) . Compared with ARID1A wild-type pts, higher expression signatures for cytotoxic T cell function, NK cells, and immune checkpoints were observed in MSS ARID1A mutated cases. ARID1A mutant cases showed higher expressions of various immune checkpoint genes (CD274, CTLA4, HAVCR2, IDO1, LAG3, PDCD1, and PDCD1LG2) compared to wild-type cases (all p < .05). All findings were observed independently in both datasets. Conclusions: In MSS CRC, ARID1A mutation is associated with a high expression of IFN-γ pathway and immune signatures (such as cytotoxic T cell function and immune checkpoint markers). The immunogenicity of ARID1A mutant cases is likely due to the increased level of neoantigens resulting from the increased rate of frame-shift mutations. Tumors with ARID1A mutation may be more susceptible to immune therapy-based treatment strategies and should likely be recognized as a unique molecular subgroup in future immune therapy trials.

scholarly journals Altered T-Cell Balance in Lymphoid Organs of a Mouse Model of Colorectal Cancer

2016 ◽  
Vol 64 (12) ◽  
pp. 753-767 ◽  
Author(s):  
Scott M. Tanner ◽  
Joseph G. Daft ◽  
Stephanie A. Hill ◽  
Colin A. Martin ◽  
Robin G. Lorenz
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Cell Function ◽  
Interleukin 17 ◽  
Intestinal Tumor ◽  
Double Positive ◽  
Tumor Immunosurveillance ◽  
T Cell Function ◽  
Ifn Γ ◽  
Cell Balance

The adenomatous polyposis coli ( APC) gene is a known tumor suppressor gene, and mice with mutations in Apc (ApcMin/+) spontaneously form multiple intestinal neoplasms. In this model of human colorectal cancer (CRC), it has been reported that CD4+ T-cell-derived interleukin 17 (IL-17) promotes intestinal tumor development, but it is not known if the Apc mutation actually directly alters T-cell function and subsequently tumor immunosurveillance. To investigate the ApcMin/+ mutation on T-cell function, flow cytometric, histochemical, and immunofluorescent studies on both wild-type (Apc+/+) and ApcMin/+ mice were performed. We identified decreased levels of interferon gamma (IFN-γ+)IL-17+ double-positive CD4+ cells in the mesenteric lymph nodes and Peyer’s patches of ApcMin/+ mice. In addition, altered levels of CD8+ cells, and changes in CD8+ production of IFN-γ and granzyme B were observed. These T-cell alterations did modify tumor immunosurveillance, as the adoptive transfer of splenocytes from ApcMin/+ animals into a chemically induced CRC model resulted in the inability to prevent epithelial dysplasia. These results suggest an altered T-cell balance in ApcMin/+ mice may disrupt intestinal homeostasis, consequently limiting intestinal tumor immunosurveillance.

scholarly journals Tpl2 Promotes Innate Cell Recruitment and Effector T Cell Differentiation To Limit Citrobacter rodentium Burden and Dissemination

2017 ◽  
Vol 85 (10) ◽  
Author(s):  
Nicole V. Acuff ◽  
Xin Li ◽  
Krishna Latha ◽  
Tamas Nagy ◽  
Wendy T. Watford
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Immune Cell ◽  
Cd4 T Cell ◽  
Citrobacter Rodentium ◽  
Wild Type ◽  
Content Type ◽  
Cell Recruitment ◽  
Ifn Γ

ABSTRACT Tumor progression locus 2 (Tpl2) is a serine-threonine kinase that regulates Th1 differentiation, secretion of the inflammatory cytokine gamma interferon (IFN-γ), and host defense against the intracellular pathogens Toxoplasma gondii, Listeria monocytogenes, and Mycobacterium tuberculosis. However, relatively little is known about the contribution of Tpl2 to Th17 differentiation and immune cell function during infection with an extracellular pathogen. The goal of this study was to determine whether Tpl2 influences the immune response generated to the extracellular bacterium Citrobacter rodentium, which induces a mixed Th1 and Th17 response. During peak infection with C. rodentium, Tpl2 −/− mice experienced greater bacterial burdens with evidence of dissemination to the liver and spleen but ultimately cleared the bacteria within 3 weeks postinfection, similar to the findings for wild-type mice. Tpl2 −/− mice also recruited fewer neutrophils and monocytes to the colon during peak infection, which correlated with increased bacterial burdens. In mixed bone marrow chimeras, Tpl2 was shown to play a T cell-intrinsic role in promoting both IFN-γ and interleukin-17A production during infection with C. rodentium. However, upon CD4 T cell transfer into Rag −/− mice, Tpl2 −/− CD4 T cells were as protective as wild-type CD4 T cells against the dissemination of bacteria and mortality. These data indicate that the enhanced bacterial burdens in Tpl2 −/− mice are not caused primarily by impairments in CD4 T cell function but result from defects in innate immune cell recruitment and function.

scholarly journals Genetic disruption of p38α Tyr323 phosphorylation prevents T-cell receptor–mediated p38α activation and impairs interferon-γ production

Blood ◽  
2009 ◽  
Vol 113 (10) ◽  
pp. 2229-2237 ◽  
Author(s):  
Ludmila Jirmanova ◽  
Dandapantula N. Sarma ◽  
Dragana Jankovic ◽  
Paul R. Mittelstadt ◽  
Jonathan D. Ashwell
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Function ◽  
Alternative Pathway ◽  
Cell Receptor ◽  
Interferon Γ ◽  
Wild Type ◽  
T Helper 1 ◽  
Ifn Γ

AbstractT cells possess a p38 activation alternative pathway in which stimulation via the antigen receptor (T-cell receptor [TCR]) induces phosphorylation of p38α and β on Tyr323. To assess the contribution of this pathway to normal T-cell function, we generated p38α knockin mice in which Tyr323 was replaced with Phe (p38αY323F). TCR-mediated stimulation failed to activate p38αY323F as measured by phosphorylation of the Thr-Glu-Tyr activation motif and p38α catalytic activity. Cell-cycle entry was delayed in TCR-stimulated p38αY323F T cells, which also produced less interferon (IFN)–γ than wild-type T cells in response to TCR-mediated but not TCR-independent stimuli. p38αY323F mice immunized with T-helper 1 (Th1)–inducing antigens generated normal Th1 effector cells, but these cells produced less IFN-γ than wild-type cells when stimulated through the TCR. Thus, the Tyr323-dependent pathway and not the classic mitogen-activated protein (MAP) kinase cascade is the physiologic means of p38α activation through the TCR and is necessary for normal Th1 function but not Th1 generation.

T cell immunoglobulin and ITIM domain, as a Potential Immune Checkpoint Target for Immunotherapy of Colorectal Cancer

IUBMB Life ◽  
2021 ◽  
Author(s):  
Mehrdad Fathi ◽  
Inna Pustokhina ◽  
Sergey V. Kuznetsov ◽  
Mars Khayrullin ◽  
Mohammad Hojjat‐Farsangi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Immune Checkpoint

scholarly journals A biomimetic assay platform for the interrogation of antigen-dependent anti-tumor T-cell function

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Jeremy To ◽  
Doug Quackenbush ◽  
Emily Rowell ◽  
Lilin Li ◽  
Connor Reed ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Function ◽  
Cell Activity ◽  
Cytotoxic T Cell ◽  
Dependent Manner ◽  
Cyclin Dependent Kinase ◽  
Histocompatibility Complex ◽  
T Cell Function ◽  
Cytolytic Granule ◽  
Screening Platform

AbstractOvercoming tumor-mediated immunosuppression and enhancing cytotoxic T-cell activity within the tumor microenvironment are two central goals of immuno-oncology (IO) drug discovery initiatives. However, exploratory assays involving immune components are often plagued by low-throughput and poor clinical relevance. Here we present an innovative ultra-high-content assay platform for interrogating T-cell-mediated killing of 3D multicellular tumor spheroids. Employing this assay platform in a chemical genomics screen of 1800 annotated compounds enabled identification of small molecule perturbagens capable of enhancing cytotoxic CD8+ T-cell activity in an antigen-dependent manner. Specifically, cyclin-dependent kinase (CDK) and bromodomain (BRD) protein inhibitors were shown to significantly augment anti-tumor T-cell function by increasing cytolytic granule and type II interferon secretion in T-cells in addition to upregulating major histocompatibility complex (MHC) expression and antigen presentation in tumor cells. The described biotechnology screening platform yields multi-parametric, clinically-relevant data and can be employed kinetically for the discovery of first-in-class IO therapeutic agents.

scholarly journals Tumor-Released Survivin Induces a Type-2 T Cell Response and Decreases Cytotoxic T Cell Function, in Vitro

2012 ◽  
Vol 6 (1) ◽  
pp. 57-68 ◽  
Author(s):  
Jessica M. S. Jutzy ◽  
Salma Khan ◽  
Malyn May Asuncion-Valenzuela ◽  
Terry-Ann M. Milford ◽  
Kimberly J. Payne ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Cell Function ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
T Cell Function

scholarly journals Gamma Interferon Production, but Not Perforin-Mediated Cytolytic Activity, of T Cells Is Required for Prevention of Toxoplasmic Encephalitis in BALB/c Mice Genetically Resistant to the Disease

2004 ◽  
Vol 72 (8) ◽  
pp. 4432-4438 ◽  
Author(s):  
Xisheng Wang ◽  
Hoil Kang ◽  
Takane Kikuchi ◽  
Yasuhiro Suzuki
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nude Mice ◽  
Genetic Resistance ◽  
Cytolytic Activity ◽  
Gamma Interferon ◽  
Toxoplasmic Encephalitis ◽  
Wild Type ◽  
Ifn Γ

ABSTRACT We previously showed the requirement of both T cells and gamma interferon (IFN-γ)-producing non-T cells for the genetic resistance of BALB/c mice to the development of toxoplasmic encephalitis (TE). In order to define the role of IFN-γ production and the perforin-mediated cytotoxicity of T cells in this resistance, we obtained immune T cells from spleens of infected IFN-γ knockout (IFN-γ−/−), perforin knockout (PO), and wild-type BALB/c mice and transferred them into infected and sulfadiazine-treated athymic nude mice, which lack T cells but have IFN-γ-producing non-T cells. Control nude mice that had not received any T cells developed severe TE and died after discontinuation of sulfadiazine treatment due to the reactivation of infection. Animals that had received immune T cells from either wild-type or PO mice did not develop TE and survived. In contrast, nude mice that had received immune T cells from IFN-γ−/− mice developed severe TE and died as early as control nude mice. T cells obtained from the spleens of animals that had received either PO or wild-type T cells produced large amounts of IFN-γ after stimulation with Toxoplasma gondii antigens in vitro. In addition, the amounts of IFN-γ mRNA expressed in the brains of PO T-cell recipients did not differ from those in wild-type T-cell recipients. Furthermore, PO mice did not develop TE after infection, and their IFN-γ production was equivalent to or higher than that of wild-type animals. These results indicate that IFN-γ production, but not perforin-mediated cytotoxic activity, by T cells is required for the prevention of TE in genetically resistant BALB/c mice.

scholarly journals Agonistic CD40 antibody therapy induces tertiary lymphoid structures but impairs the response to immune checkpoint blockade in glioma

2021 ◽  
Author(s):  
Luuk van Hooren ◽  
Alessandra Vaccaro ◽  
Mohanraj Ramachandran ◽  
Konstantinos Vazaios ◽  
Sylwia Libard ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Antibody Therapy ◽  
Immune Checkpoint Blockade ◽  
Cytotoxic T Cell ◽  
Systemic Delivery ◽  
T Cell Infiltration ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

AbstractGliomas are brain tumors characterized by immunosuppression. Immunostimulatory agonistic CD40 antibodies (αCD40) are in clinical development for solid tumors but are yet to be evaluated for glioma. Here, systemic delivery of αCD40 led to cytotoxic T cell dysfunction and impaired the response to immune checkpoint inhibitors in preclinical glioma models. This was associated with an accumulation of suppressive CD11b+ B cells. However, αCD40 also induced tertiary lymphoid structures (TLS). In human glioma, TLS correlated with increased T cell infiltration indicating enhanced immune responses. Our work unveils the pleiotropic effects of αCD40 therapy in glioma, which is of high clinical relevance.

scholarly journals Cancer immune therapy with PD-1-dependent CD137 co-stimulation provides localized tumour killing without systemic toxicity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yunqian Qiao ◽  
Yangmin Qiu ◽  
Jie Ding ◽  
Nana Luo ◽  
Hao Wang ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Liver Toxicity ◽  
Nk Cell ◽  
Immune Therapy ◽  
Clinical Development ◽  
Cell Surface Receptor ◽  
Natural Ligand

AbstractExpression of the cell surface receptor CD137 has been shown to enhance anti-cancer T cell function via engagement with its natural ligand 4-1BBL. CD137 ligation with engineered ligands has emerged as a cancer immunotherapy strategy, yet clinical development of agonists has been hindered by either toxicity or limited efficacy. Here we show that a CD137/PD-1 bispecific antibody, IBI319, is able to overcome these limitations by coupling CD137 activation to PD-1-crosslinking. In CT26 and MC38 syngeneic mouse tumour models, IBI319 restricts T cell co-stimulation to PD-1-rich microenvironments, such as tumours and tumour-draining lymph nodes, hence systemic (liver) toxicity arising from generalised T cell activation is reduced. Besides limiting systemic T cell co-stimulation, the anti-PD-1 arm of IBI319 also exhibits checkpoint blockade functions, with an overall result of T and NK cell infiltration into tumours. Toxicology profiling in non-human primates shows that IBI319 is a well-tolerated molecule with IgG-like pharmacokinetic properties, thus a suitable candidate for further clinical development.

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