scholarly journals Multi-model preclinical platform predicts clinical response of melanoma to immunotherapy

2019 ◽  
Author(s):  
Eva Pérez-Guijarro ◽  
Howard H. Yang ◽  
Romina E. Araya ◽  
Rajaa El Meskini ◽  
Helen T. Michael ◽  
...  
Keyword(s):  
Immune Cell ◽  
Treatment Strategies ◽  
Predictive Biomarkers ◽  
Improve Patient Care ◽  
Immune Checkpoint Blockade ◽  
Cell Dysfunction ◽  
Clinical Observations ◽  
Genome Wide ◽  
T Cell Dysfunction ◽  
Differentiation Status

Although immunotherapy has revolutionized cancer treatment, only a subset of patients demonstrates durable clinical benefit. Definitive predictive biomarkers and targets to overcome resistance remain unidentified, underscoring the urgency to develop reliable immunocompetent models for mechanistic assessment. Here we characterize a panel of syngeneic mouse models representing the main molecular and phenotypic subtypes of human melanomas and exhibiting their range of responses to immune checkpoint blockade (ICB). Comparative analysis of genomic, transcriptomic and tumor-infiltrating immune cell profiles demonstrated alignment with clinical observations and validated the correlation of T cell dysfunction and exclusion programs with resistance. Notably, genome-wide expression analysis uncovered a melanocytic plasticity signature predictive of patient outcome in response to ICB, suggesting that the multipotency and differentiation status of melanoma can determine ICB benefit. Our comparative preclinical platform recapitulates melanoma clinical behavior and can be employed to identify new mechanisms and treatment strategies to improve patient care.

scholarly journals Immune metabolism in PD-1 blockade-based cancer immunotherapy

2020 ◽  
Vol 33 (1) ◽  
pp. 17-26
Author(s):  
Alok Kumar ◽  
Kenji Chamoto
Keyword(s):  
T Cell ◽  
Cancer Immunotherapy ◽  
Cancer Cell ◽  
Metabolic Regulation ◽  
Immune Cell ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Abstract Energy metabolism plays an important role in proliferating cells. Recent reports indicate that metabolic regulation or metabolic products can control immune cell differentiation, fate and reactions. Cancer immunotherapy based on blockade of programmed cell death protein 1 (PD-1) has been used worldwide, but a significant fraction of patients remain unresponsive. Therefore, clarifying the mechanisms and overcoming the unresponsiveness are urgent issues. Because cancer immunity consists of interactions between the cancer and host immune cells, there has recently been a focus on the metabolic interactions and/or competition between the tumor and the immune system to address these issues. Cancer cells render their microenvironment immunosuppressive, driving T-cell dysfunction or exhaustion, which is advantageous for cancer cell survival. However, accumulating mechanistic evidence of T-cell and cancer cell metabolism has gradually revealed that controlling the metabolic pathways of either type of cell can overcome T-cell dysfunction and reprogram the metabolic balance in the tumor microenvironment. Here, we summarize the role of immune metabolism in T-cell-based immune surveillance and cancer immune escape. This new concept has boosted the development of combination therapy and predictive biomarkers in cancer immunotherapy with immune checkpoint inhibitors.

scholarly journals CAR T cells for solid tumors: genome-wide dysfunction signature confirms value of c-Jun overexpression, but signals heterogeneity

2020 ◽  
Author(s):  
Mostapha Benhenda
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
T Cell Therapy ◽  
Cell Dysfunction ◽  
Car T Cells ◽  
Genome Wide ◽  
A Genome ◽  
Car T ◽  
T Cell Dysfunction

AbstractChimeric antigen receptor (CAR) T cells still have limited effects in cancer, and especially in solid tumors, due to T cell dysfunction and exhaustion. CAR T cells overexpressing c-Jun (JUN CAR T cells) have been introduced to solve this problem. In this paper, we analyze JUN CAR T cells scRNA-seq data in solid tumors, by applying a genome-wide signature of T cell dysfunction, TID. This signature comes from the bulk RNA-seq signature TIDE, introduced to predict immune checkpoint inhibitor response. Our analysis confirms that on average, JUN CAR T cells are less dysfunctional than non-JUN CAR T cells. However, it also shows heterogeneity within JUN CAR T cells, which brings uncertainty about possible tumor resistance. We conclude that genome-wide dysfunction signature TID helps de-risking CAR T cell therapy for solid tumors.

scholarly journals Emerging role of tumor-derived extracellular vesicles in T cell suppression and dysfunction in the tumor microenvironment

2021 ◽  
Vol 9 (10) ◽  
pp. e003217
Author(s):  
Feiya Ma ◽  
Jensen Vayalil ◽  
Grace Lee ◽  
Yuqi Wang ◽  
Guangyong Peng
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Extracellular Vesicles ◽  
Tumor Immunity ◽  
Cell Metabolism ◽  
Immune Checkpoint Blockade ◽  
Intrinsic Factors ◽  
Cell Dysfunction ◽  
T Cell Dysfunction ◽  
Immune Checkpoint Blockade Antibodies

Immunotherapeutic drugs including immune checkpoint blockade antibodies have been approved to treat patients in many types of cancers. However, some patients have little or no reaction to the immunotherapy drugs. The mechanisms underlying resistance to tumor immunotherapy are complicated and involve multiple aspects, including tumor-intrinsic factors, formation of immunosuppressive microenvironment, and alteration of tumor and stromal cell metabolism in the tumor microenvironment. T cell is critical and participates in every aspect of antitumor response, and T cell dysfunction is a severe barrier for effective immunotherapy for cancer. Emerging evidence indicates that extracellular vesicles (EVs) secreted by tumor is one of the major factors that can induce T cell dysfunction. Tumor-derived EVs are widely distributed in serum, tissues, and the tumor microenvironment of patients with cancer, which serve as important communication vehicles for cancer cells. In addition, tumor-derived EVs can carry a variety of immune suppressive signals driving T cell dysfunction for tumor immunity. In this review, we explore the potential mechanisms employed by tumor-derived EVs to control T cell development and effector function within the tumor microenvironment. Especially, we focus on current understanding of how tumor-derived EVs molecularly and metabolically reprogram T cell fates and functions for tumor immunity. In addition, we discuss potential translations of targeting tumor-derived EVs to reconstitute suppressive tumor microenvironment or to develop antigen-based vaccines and drug delivery systems for cancer immunotherapy.

scholarly journals T-cell dysfunction in chronic lymphocytic leukemia from an epigenetic perspective

Haematologica ◽  
2021 ◽  
Author(s):  
Fleur S. Peters ◽  
Jonathan C. Strefford ◽  
Eric Eldering ◽  
Arnon P. Kater
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Immune Cell ◽  
Lymphocytic Leukemia ◽  
T Cell Therapy ◽  
High Expectations ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Cellular immunotherapeutic approaches such as chimeric antigen receptor (CAR) T-cell therapy in chronic lymphocytic leukemia (CLL) thus far have not met the high expectations. Therefore it is essential to better understand the molecular mechanisms of CLLinduced T-cell dysfunction. Even though a significant number of studies are available on T-cell function and dysfunction in CLL patients, none examine dysfunction at the epigenomic level. In non-malignant T-cell research, epigenomics is widely employed to define the differentiation pathway into T-cell exhaustion. Additionally, metabolic restrictions in the tumor microenvironment that cause T-cell dysfunction are often mediated by epigenetic changes. With this review paper we argue that understanding the epigenetic (dys)regulation in T cells of CLL patients should be leveled to the knowledge we currently have of the neoplastic B cells themselves. This will permit a complete understanding of how these immune cell interactions regulate T- and B-cell function. Here we relate the cellular and phenotypic characteristics of CLL-induced T-cell dysfunction to epigenetic studies of T-cell regulation emerging from chronic viral infection and tumor models. This paper proposes a framework for future studies into the epigenetic regulation of CLL-induced Tcell dysfunction, knowledge that will help to guide improvements in the utility of autologous T-cell based therapies in CLL.

scholarly journals HDAC6 Inhibition Alleviates CLL-Induced T-Cell Dysfunction and Enhances Immune Checkpoint Blockade Efficacy in the Eμ-TCL1 Model

2020 ◽  
Vol 11 ◽  
Author(s):  
Kamira Maharaj ◽  
John J. Powers ◽  
Melanie Mediavilla-Varela ◽  
Alex Achille ◽  
Wael Gamal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Tumor Burden ◽  
Checkpoint Blockade ◽  
Cell Phenotype ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Development of chronic lymphocytic leukemia (CLL) is associated with severe immune dysfunction. T-cell exhaustion, immune checkpoint upregulation, and increase of regulatory T cells contribute to an immunosuppressive tumor microenvironment. As a result, CLL patients are severely susceptible to infectious complications that increase morbidity and mortality. CLL B-cell survival is highly dependent upon interaction with the supportive tumor microenvironment. It has been postulated that the reversal of T-cell dysfunction in CLL may be beneficial to reduce tumor burden. Previous studies have also highlighted roles for histone deacetylase 6 (HDAC6) in regulation of immune cell phenotype and function. Here, we report for the first time that HDAC6 inhibition exerts beneficial immunomodulatory effects on CLL B cells and alleviates CLL-induced immunosuppression of CLL T cells. In the Eμ-TCL1 adoptive transfer murine model, genetic silencing or inhibition of HDAC6 reduced surface expression of programmed death-ligand 1 (PD-L1) on CLL B cells and lowered interleukin-10 (IL-10) levels. This occurred concurrently with a bolstered T-cell phenotype, demonstrated by alteration of coinhibitory molecules and activation status. Analysis of mice with similar tumor burden indicated that the majority of T-cell changes elicited by silencing or inhibition of HDAC6 in vivo are likely secondary to decrease of tumor burden and immunomodulation of CLL B cells. The data reported here suggest that CLL B cell phenotype may be altered by HDAC6-mediated hyperacetylation of the chaperone heat shock protein 90 (HSP90) and subsequent inhibition of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. Based on the beneficial immunomodulatory activity of HDAC6 inhibition, we rationalized that HDAC6 inhibitors could enhance immune checkpoint blockade in CLL. Conclusively, combination treatment with ACY738 augmented the antitumor efficacy of anti-PD-1 and anti-PD-L1 monoclonal antibodies in the Eμ-TCL1 adoptive transfer murine model. These combinatorial antitumor effects coincided with an increased cytotoxic CD8+ T-cell phenotype. Taken together, these data highlight a role for HDAC inhibitors in combination with immunotherapy and provides the rationale to investigate HDAC6 inhibition together with immune checkpoint blockade for treatment of CLL patients.

scholarly journals T-Cell Dysfunction as a Limitation of Adoptive Immunotherapy: Current Concepts and Mitigation Strategies

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 598
Author(s):  
Valérie Janelle ◽  
Jean-Sébastien Delisle
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Ex Vivo ◽  
Genetically Engineered ◽  
Mitigation Strategies ◽  
Cellular Immunotherapy ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Over the last decades, cellular immunotherapy has revealed its curative potential. However, inherent physiological characteristics of immune cells can limit the potency of this approach. Best defined in T cells, dysfunction associated with terminal differentiation, exhaustion, senescence, and activation-induced cell death, undermine adoptive cell therapies. In this review, we concentrate on how the multiple mechanisms that articulate the various forms of immune dysfunction impact cellular therapies primarily involving conventional T cells, but also other lymphoid subtypes. The repercussions of immune cell dysfunction across the full life cycle of cell therapy, from the source material, during manufacturing, and after adoptive transfer, are discussed, with an emphasis on strategies used during ex vivo manipulations to limit T-cell dysfunction. Applicable to cellular products prepared from native and unmodified immune cells, as well as genetically engineered therapeutics, the understanding and potential modulation of dysfunctional features are key to the development of improved cellular immunotherapies.

scholarly journals Dynamic Expressions of TIGIT on Splenic T Cells and TIGIT-Mediated Splenic T Cell Dysfunction of Mice With Chronic Toxoplasma gondii Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Haoran Li ◽  
Jing Zhang ◽  
Changwei Su ◽  
Xiaowei Tian ◽  
Xuefang Mei ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
Cell Function ◽  
Immune Cell ◽  
Rt Pcr ◽  
Cell Dysfunction ◽  
T Cell Dysfunction ◽  
Toxoplasma Gondii Infection ◽  
Cellular Immune

As an immunosuppressive receptor, T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) play a critical part in cellular immune regulation mediated by pathogen infection. Whereas, TIGIT expression on splenic T cells in hosts infected with Toxoplasma gondii cysts has not been studied. In this study, we detected TIGIT expression and the changes of immune function in the spleen by flow cytometry and real-time PCR (RT-PCR). We found that TIGIT expression on splenic T cells increased significantly post infection. At the same time, splenic TIGIT+TCM cells were activated and transformed into TIGIT+TEM cells during the infection, and the cytotoxicity of TIGIT+ T cells was reduced in the later stage of infection. This study shows that chronic T. gondii infection can upregulate TIGIT expression on the surface of T cells and affect immune cell function.

scholarly journals Optimizing T Cell-Based Therapy for Glioblastoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Aida Karachi ◽  
Farhad Dastmalchi ◽  
Saina Nazarian ◽  
Jianping Huang ◽  
Elias J. Sayour ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Treatment Strategies ◽  
Cell Dysfunction ◽  
Cell Based Therapy ◽  
Car T ◽  
Transfer Strategies ◽  
T Cell Dysfunction ◽  
T Cell Transfer

Evading T cell surveillance is a hallmark of cancer. Patients with solid tissue malignancy, such as glioblastoma (GBM), have multiple forms of immune dysfunction, including defective T cell function. T cell dysfunction is exacerbated by standard treatment strategies such as steroids, chemotherapy, and radiation. Reinvigoration of T cell responses can be achieved by utilizing adoptively transferred T cells, including CAR T cells. However, these cells are at risk for depletion and dysfunction as well. This review will discuss adoptive T cell transfer strategies and methods to avoid T cell dysfunction for the treatment of brain cancer.

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