scholarly journals Role of Bladder Cancer Metabolic Reprogramming in the Effectiveness of Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 288
Author(s):  
Mathijs P. Scholtes ◽  
Florus C. de Jong ◽  
Tahlita C. M. Zuiverloon ◽  
Dan Theodorescu
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Metabolic Reprogramming ◽  
Host Cells ◽  
T Cell Therapy ◽  
Literature Searches ◽  
The Impact

Metabolic reprogramming (MR) is an upregulation of biosynthetic and bioenergetic pathways to satisfy increased energy and metabolic building block demands of tumors. This includes glycolytic activity, which deprives the tumor microenvironment (TME) of nutrients while increasing extracellular lactic acid. This inhibits cytotoxic immune activity either via direct metabolic competition between cancer cells and cytotoxic host cells or by the production of immune-suppressive metabolites such as lactate or kynurenine. Since immunotherapy is a major treatment option in patients with metastatic urothelial carcinoma (UC), MR may have profound implications for the success of such therapy. Here, we review how MR impacts host immune response to UC and the impact on immunotherapy response (including checkpoint inhibitors, adaptive T cell therapy, T cell activation, antigen presentation, and changes in the tumor microenvironment). Articles were identified by literature searches on the keywords or references to “UC” and “MR”. We found several promising therapeutic approaches emerging from preclinical models that can circumvent suppressive MR effects on the immune system. A select summary of active clinical trials is provided with examples of possible options to enhance the effectiveness of immunotherapy. In conclusion, the literature suggests manipulating the MR is feasible and may improve immunotherapy effectiveness in UC.

Novel synthetic immune modulators for the activation of tumor antigen-specific T cells.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15203-e15203
Author(s):  
Di Zhang ◽  
Lihua Shi ◽  
Susan Tam ◽  
Man-Cheong Fung
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Tumor Antigen ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Adoptive T Cell Therapy ◽  
In Vivo Studies ◽  
Target Specificity ◽  
T Cell Therapy

e15203 Background: Although checkpoint inhibitor immunotherapy and adoptive T-cell therapy revolutionized cancer treatments, such approaches suffer either from lack of target specificity for checkpoint inhibitors or inability to target intracellular tumor-related antigens from CAR-T therapy. Here, we report the development of novel Tavo Immune Modulator (TIM) biologics molecules which can specifically recognize tumor antigen-specific T cells through an engineered pMHC complex with peptides derived from intracellular tumor-related antigens. These molecules can selectively activate such T cells through engineered T cell co-stimulatory modulators for enhanced tumor cell killing. Methods: NY-ESO-1 and MAGE-A10 TIM molecules were constructed as fusions of HLA-A*02:01 MHC complexed with either NY-ESO-1 (157-165) or MAGE-A10 (254-262) epitope peptides at the N-termini and various T cell costimulatory modulators at the C-termini of IgG heavy and light chains. TIM molecules were expressed in Expi293 cells and purified by Protein A affinity chromatography. Specific binding of TIM with cancer specific T cells was evaluated by immunostaining. The activation and proliferation of tumor specific CD8+ T cells were confirmed in T cell activation and recall assays. Results: Both NY-ESO-1 and MAGE-A10 specific TIM molecules were generated which recognized corresponding tumor specific T cells. NY-ESO-1 TIM engineered with IL2 could activate NY-ESO-1 specific CD8+ T cell exclusively. Engineering additional T cell costimulatory factors along with IL2 on NY-ESO-1 TIM molecule could further boost T cell proliferation and activation in T cell recall assays. Besides NY-ESO-1, combinations of T cell costimulatory factors with MAGE-A10 TIM molecules enhanced specific T cell activation. Additional in vitro and in vivo studies are ongoing to demonstrate efficacy of such novel TIM molecules in eliminating different types of NY-ESO-1 and MAGE-A10 which are over-expressed on tumor cells. Conclusions: This study demonstrates the utility of NY-ESO-1 and MAGE-A10 TIM molecules in the selective recognition and activation of tumor antigen-specific T cells. Such novel biologics molecules may provide target specificity in tumor treatment, and potential targeting of intracellular tumor-related antigens presented as peptides in MHC complexes on cell surfaces. Selective activation of tumor-specific T cells may provide a unique method for the treatment of various solid tumors and warrants further investigation.

scholarly journals Cell Intrinsic and Systemic Metabolism in Tumor Immunity and Immunotherapy

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 852 ◽  
Author(s):  
Michael F. Coleman ◽  
Alyssa J. Cozzo ◽  
Alexander J. Pfeil ◽  
Suhas K. Etigunta ◽  
Stephen D. Hursting
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Metabolism ◽  
Immune Surveillance ◽  
Therapy Outcomes ◽  
Host Metabolism ◽  
The Impact

Immune checkpoint inhibitor (ICI) therapy has shown extraordinary promise at treating cancers otherwise resistant to treatment. However, for ICI therapy to be effective, it must overcome the metabolic limitations of the tumor microenvironment. Tumor metabolism has long been understood to be highly dysregulated, with potent immunosuppressive effects. Moreover, T cell activation and longevity within the tumor microenvironment are intimately tied to T cell metabolism and are required for the long-term efficacy of ICI therapy. We discuss in this review the intersection of metabolic competition in the tumor microenvironment, T cell activation and metabolism, the roles of tumor cell metabolism in immune evasion, and the impact of host metabolism in determining immune surveillance and ICI therapy outcomes. We also discussed the effects of obesity and calorie restriction—two important systemic metabolic perturbations that impact intrinsic metabolic pathways in T cells as well as cancer cells.

scholarly journals Computational verification of large logical models – application to the prediction of T cell response to checkpoint inhibitors

2020 ◽  
Author(s):  
Céline Hernandez ◽  
Morgane Thomas-Chollier ◽  
Aurélien Naldi ◽  
Denis Thieffry
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
T Cell Response ◽  
Model Verification ◽  
Dynamical Analysis ◽  
Computational Systems Biology ◽  
Analysis Methods ◽  
The Impact

ABSTRACTAt the crossroad between biology and mathematical modelling, computational systems biology can contribute to a mechanistic understanding of high-level biological phenomenon. But as knowledge accumulates, the size and complexity of mathematical models increase, calling for the development of efficient dynamical analysis methods. Here, we propose the use of two approaches for the development and analysis of complex cellular network models.A first approach, called “model verification” and inspired by unitary testing in software development, enables the formalisation and automated verification of validation criteria for whole models or selected sub-parts. When combined with efficient analysis methods, this approach is suitable for continuous testing, thereby greatly facilitating model development.A second approach, called “value propagation”, enables efficient analytical computation of the impact of specific environmental or genetic conditions on the dynamical behaviour of some models.We apply these two approaches to the delineation and the analysis of a comprehensive model for T cell activation, taking into account CTLA4 and PD-1 checkpoint inhibitory pathways. While model verification greatly eases the delineation of logical rules complying with a set of dynamical specifications, propagation provides interesting insights into the different potential of CTLA4 and PD-1 immunotherapies.Both methods are implemented and made available in the all-inclusive CoLoMoTo Docker image, while the different steps of the model analysis are fully reported in two companion interactive jupyter notebooks, thereby ensuring the reproduction of our results.

scholarly journals 692 Tim-3 expression drives phenotypic and functional changes in Treg in secondary lymphoid organs and the tumor microenvironment, effecting tumor burden

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A720-A720
Author(s):  
Hridesh Banerjee ◽  
Hector Nieves-Rosado ◽  
Benjamin Murter ◽  
Lawrence Kane
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Mouse Model ◽  
Tumor Immunity ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Burden ◽  
Lymphoid Organs ◽  
Functional Changes ◽  
The Impact

BackgroundRegulatory T cells (T reg) are critical mediators of self-tolerance but can also limit effective anti-tumor immunity. We and others previously reported that 40–60% percent of T reg-infiltrating head and neck cancer (HNC) and other tumors highly express Tim-3, compared with about 5% in lymphoid organs, it therefore gets imperative to characterize if Tim-3 is driving any T reg specific function in tumor microenvironment and under homeostasis.MethodsUsing a conditional TIM-3 inducible and knockout mouse model developed in our lab, we have performed syngeneic tumor challenges in T reg-specific Tim-3 transgenic and knockout mice (FoxP3ERT2CreSFS-Tim-3 and FoxP3ERT2Cre-FLEX4). We have also characterized the tumor immune infiltrate of these mice to understand the impact of T reg specific Tim-3induction and deficiency on the immune landscape.ResultsTim-3 induction on T reg leads to rapid growth associated with higher progression of CD8 compartment towards exhaustion, while TIm-3 knockout in T reg specific manner leads top overall decline in T reg compartment in tumors associated with lower exhaustion in the CD8 compartment and decrease in tumor burden,ConclusionsTumor-infiltrating Tim-3+ Treg have enhanced suppressive function and display a more effector-like phenotype. Using a novel mouse model with cell type-specific Tim-3 expression, we show here that expression of Tim-3 by Treg is sufficient to drive Treg to a more effector-like phenotype, and increases suppressive activity, effector T cell exhaustion and tumor growth. We also show that inducible deletion of Tim-3 specifically from Treg enhances anti-tumor immunity and decrease in tumor burden along with a decrease in tumor associated Treg compartment. These findings may help to reconcile previous reports that some Tim-3 antibodies enhance T cell responses in vivo, while expression of Tim-3 has a cell-intrinsic ability to enhance TCR signaling and T cell activation. A major role of Tim-3 was found to be mediated through IL-10 and IL-10 R pathway in both Treg and CD8 compartment. Thus, we propose that Tim-3 regulates anti-tumor immunity at least in part through enhancement of Treg function. To our knowledge, this is the first example in which expression of a single co-stimulatory molecule is sufficient to drive differentiation of Treg in this manner.AcknowledgementsWe acknoledge Dr. Robert L. Ferris and Dr. Greg M. Delgoffe for their inputs and guidance with human and metabolism associated experiments.

scholarly journals Imaging of tumour response to immunotherapy

2020 ◽  
Vol 4 (1) ◽  
Author(s):  
Clarisse Dromain ◽  
Catherine Beigelman ◽  
Chiara Pozzessere ◽  
Rafael Duran ◽  
Antonia Digklia
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Tumour Response ◽  
Predictive Biomarkers ◽  
Adoptive T Cell Therapy ◽  
Imaging Features ◽  
T Cell Therapy ◽  
Wide Range

AbstractA wide range of cancer immunotherapy approaches has been developed including non-specific immune-stimulants such as cytokines, cancer vaccines, immune checkpoint inhibitors (ICIs), and adoptive T cell therapy. Among them, ICIs are the most commonly used and intensively studied. Since 2011, these drugs have received marketing authorisation for melanoma, lung, bladder, renal, and head and neck cancers, with remarkable and long-lasting treatment response in some patients. The novel mechanism of action of ICIs, with immune and T cell activation, leads to unusual patterns of response on imaging, with the advent of so-called pseudoprogression being more pronounced and frequently observed when compared to other anticancer therapies. Pseudoprogression, described in about 2–10% of patients treated with ICIs, corresponds to an increase of tumour burden and/or the appearance of new lesions due to infiltration by activated T cells before the disease responds to therapy. To overcome the limitation of response evaluation criteria in solid tumors (RECIST) to assess these specific changes, new imaging criteria—so-called immune-related response criteria and then immune-related RECIST (irRECIST)—were proposed. The major modification involved the inclusion of the measurements of new target lesions into disease assessments and the need for a 4-week re-assessment to confirm or not confirm progression. The RECIST working group introduced the new concept of “unconfirmed progression”, into the irRECIST. This paper reviews current immunotherapeutic approaches and summarises radiologic criteria to evaluate new patterns of response to immunotherapy. Furthermore, imaging features of immunotherapy-related adverse events and available predictive biomarkers of response are presented.

scholarly journals Dendritic Cell Tumor Vaccination via Fc Gamma Receptor Targeting: Lessons Learned from Pre-Clinical and Translational Studies

Vaccines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 409
Author(s):  
Enrique Gómez Alcaide ◽  
Sinduya Krishnarajah ◽  
Fabian Junker
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tumor Antigens ◽  
Checkpoint Inhibitors ◽  
Critical Role ◽  
Lessons Learned ◽  
Antigen Delivery ◽  
Tumor Vaccination ◽  
Translational Studies

Despite significant recent improvements in the field of immunotherapy, cancer remains a heavy burden on patients and healthcare systems. In recent years, immunotherapies have led to remarkable strides in treating certain cancers. However, despite the success of checkpoint inhibitors and the advent of cellular therapies, novel strategies need to be explored to (1) improve treatment in patients where these approaches fail and (2) make such treatments widely and financially accessible. Vaccines based on tumor antigens (Ag) have emerged as an innovative strategy with the potential to address these areas. Here, we review the fundamental aspects relevant for the development of cancer vaccines and the critical role of dendritic cells (DCs) in this process. We first offer a general overview of DC biology and routes of Ag presentation eliciting effective T cell-mediated immune responses. We then present new therapeutic avenues specifically targeting Fc gamma receptors (FcγR) as a means to deliver antigen selectively to DCs and its effects on T-cell activation. We present an overview of the mechanistic aspects of FcγR-mediated DC targeting, as well as potential tumor vaccination strategies based on preclinical and translational studies. In particular, we highlight recent developments in the field of recombinant immune complex-like large molecules and their potential for DC-mediated tumor vaccination in the clinic. These findings go beyond cancer research and may be of relevance for other disease areas that could benefit from FcγR-targeted antigen delivery, such as autoimmunity and infectious diseases.

scholarly journals The impact of age on the prognostic capacity of CD8+ T-cell activation during suppressive antiretroviral therapy

AIDS ◽  
2013 ◽  
Vol 27 (13) ◽  
pp. 2101-2110 ◽  
Author(s):  
Judith J. Lok ◽  
Peter W. Hunt ◽  
Ann C. Collier ◽  
Constance A. Benson ◽  
Mallory D. Witt ◽  
...  
Keyword(s):  
T Cell ◽  
Antiretroviral Therapy ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
The Impact

Development and characterization of a HCMV multiantigen therapeutic vaccine for GBM using the UNITE platform.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14565-e14565
Author(s):  
Amit Adhikari ◽  
Juliete Macauley ◽  
Yoshimi Johnson ◽  
Mike Connolly ◽  
Tim Coleman ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Mouse Model ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
T Cell Response

e14565 Background: Glioblastoma (GBM) is an aggressive form of brain cancer with a median survival of 15 months which has remained unchanged despite technological advances in the standard of care. GBM cells specifically express human cytomegalovirus (HCMV) proteins providing a unique opportunity for targeted therapy. Methods: We utilized our UNITE (UNiversal Intracellular Targeted Expression) platform to develop a multi-antigen DNA vaccine (ITI-1001) that codes for the HCMV proteins- pp65, gB and IE-1. The UNITE platform involves lysosomal targeting technology, fusing lysosome-associated protein 1 (LAMP1) with target antigens resulting in increased antigen presentation by MHC-I and II. ELISpot, flow cytometry and ELISA techniques were used to evaluate the vaccine immunogenicity and a syngeneic, orthotopic GBM mouse model that expresses HCMV proteins was used for efficacy studies. The tumor microenvironment studies were done using flow cytometry and MSD assay. Results: ITI-1001 vaccination showed a robust antigen-specific CD4 and CD8 T cell response in addition to a strong humoral response. Using GBM mouse model, therapeutic treatment of ITI-1001 vaccine resulted in ̃56% survival with subsequent long-term immunity. Investigating the tumor microenvironment showed significant CD4 T cell infiltration as well as enhanced Th1 and CD8 T cell activation. Regulatory T cells were also upregulated upon ITI-1001 vaccination and would be an attractive target to further improve this therapy. In addition, tumor burden negatively correlated with number of activated CD4 T cells (CD4 IFNγ+) reiterating the importance of CD4 activation in ITI-1001 efficacy and potentially identifying treatment responders and non-responders. Further characterization of these two groups showed high infiltration of CD3+, CD4+ and CD8+ T cells in responders compared with non- responders along with higher CD8 T cell activation. Conclusions: Thus, we show that vaccination with HCMV antigens using the ITI-1001-UNITE platform generates strong cellular and humoral immune responses, triggering significant anti-tumor activity that leads to enhanced survival in mice with GBM.

scholarly journals Diacylglycerol kinase ζ limits IL-2-dependent control of PD-1 expression in tumor-infiltrating T lymphocytes

2020 ◽  
Vol 8 (2) ◽  
pp. e001521
Author(s):  
Javier Arranz-Nicolás ◽  
Miguel Martin-Salgado ◽  
Cristina Rodríguez-Rodríguez ◽  
Rosa Liébana ◽  
Maria C Moreno-Ortiz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Therapeutic Potential ◽  
Interleukin 2 ◽  
Tumor Rejection ◽  
Cytotoxic T Cell ◽  
Adenocarcinoma Cells ◽  
The Impact

BackgroundThe inhibitory functions triggered by the programmed cell death-1 (PD-1) receptor following binding to its ligand (PD-L1) protect healthy organs from cytotoxic T cells, and neutralize antitumor T cell attack. Antibody-based therapies to block PD-1/PD-L1 interaction have yielded notable results, but most patients eventually develop resistance. This failure is attributed to CD8+ T cells achieving hyporesponsive states from which recovery is hardly feasible. Dysfunctional T cell phenotypes are favored by a sustained imbalance in the diacylglycerol (DAG)- and Ca2+-regulated transcriptional programs. In mice, DAG kinase ζ (DGKζ) facilitates DAG consumption, limiting T cell activation and cytotoxic T cell responses. DGKζ deficiency facilitates tumor rejection in mice without apparent adverse autoimmune effects. Despite its therapeutic potential, little is known about DGKζ function in human T cells, and no known inhibitors target this isoform.MethodsWe used a human triple parameter reporter cell line to examine the consequences of DGKζ depletion on the transcriptional restriction imposed by PD-1 ligation. We studied the effect of DGKζ deficiency on PD-1 expression dynamics, as well as the impact of DGKζ absence on the in vivo growth of MC38 adenocarcinoma cells.ResultsWe demonstrate that DGKζ depletion enhances DAG-regulated transcriptional programs, promoting interleukin-2 production and partially counteracting PD-1 inhibitory functions. DGKζ loss results in limited PD-1 expression and enhanced expansion of cytotoxic CD8+ T cell populations. This is observed even in immunosuppressive milieus, and correlates with the reduced ability of MC38 adenocarcinoma cells to form tumors in DGKζ-deficient mice.ConclusionsOur results, which define a role for DGKζ in the control of PD-1 expression, confirm DGKζ potential as a therapeutic target as well as a biomarker of CD8+ T cell dysfunctional states.

scholarly journals MALT1 Controls Attenuated Rabies Virus by Inducing Early Inflammation and T Cell Activation in the Brain

2018 ◽  
Vol 92 (8) ◽  
Author(s):  
E. Kip ◽  
J. Staal ◽  
L. Verstrepen ◽  
H. G. Tima ◽  
S. Terryn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Infection ◽  
Rabies Virus ◽  
T Cell Activation ◽  
Therapeutic Target ◽  
Cell Activation ◽  
Wild Type ◽  
The Impact ◽  
The Brain

ABSTRACTMALT1 is involved in the activation of immune responses, as well as in the proliferation and survival of certain cancer cells. MALT1 acts as a scaffold protein for NF-κB signaling and a cysteine protease that cleaves substrates, further promoting the expression of immunoregulatory genes. Deregulated MALT1 activity has been associated with autoimmunity and cancer, implicating MALT1 as a new therapeutic target. Although MALT1 deficiency has been shown to protect against experimental autoimmune encephalomyelitis, nothing is known about the impact of MALT1 on virus infection in the central nervous system. Here, we studied infection with an attenuated rabies virus, Evelyn-Rotnycki-Abelseth (ERA) virus, and observed increased susceptibility with ERA virus in MALT1−/−mice. Indeed, after intranasal infection with ERA virus, wild-type mice developed mild transient clinical signs with recovery at 35 days postinoculation (dpi). Interestingly, MALT1−/−mice developed severe disease requiring euthanasia at around 17 dpi. A decreased induction of inflammatory gene expression and cell infiltration and activation was observed in MALT1−/−mice at 10 dpi compared to MALT1+/+infected mice. At 17 dpi, however, the level of inflammatory cell activation was comparable to that observed in MALT1+/+mice. Moreover, MALT1−/−mice failed to produce virus-neutralizing antibodies. Similar results were obtained with specific inactivation of MALT1 in T cells. Finally, treatment of wild-type mice with mepazine, a MALT1 protease inhibitor, also led to mortality upon ERA virus infection. These data emphasize the importance of early inflammation and activation of T cells through MALT1 for controlling the virulence of an attenuated rabies virus in the brain.IMPORTANCERabies virus is a neurotropic virus which can infect any mammal. Annually, 59,000 people die from rabies. Effective therapy is lacking and hampered by gaps in the understanding of virus pathogenicity. MALT1 is an intracellular protein involved in innate and adaptive immunity and is an interesting therapeutic target because MALT1-deregulated activity has been associated with autoimmunity and cancers. The role of MALT1 in viral infection is, however, largely unknown. Here, we study the impact of MALT1 on virus infection in the brain, using the attenuated ERA rabies virus in different models of MALT1-deficient mice. We reveal the importance of MALT1-mediated inflammation and T cell activation to control ERA virus, providing new insights in the biology of MALT1 and rabies virus infection.

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