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.

Combination cancer immunotherapy targeting PD-1 and GITR can rescue CD8+T cell dysfunction and maintain memory phenotype

2018 ◽  
Vol 3 (29) ◽  
pp. eaat7061 ◽  
Author(s):  
Bei Wang ◽  
Wen Zhang ◽  
Vladimir Jankovic ◽  
Jacquelynn Golubov ◽  
Patrick Poon ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
Cancer Immunotherapy ◽  
Effector Memory ◽  
Cell Phenotype ◽  
Checkpoint Inhibition ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Most patients with cancer do not develop durable antitumor responses after programmed cell death protein 1 (PD-1) or programmed cell death ligand 1(PD-L1) checkpoint inhibition monotherapy because of an ephemeral reversal of T cell dysfunction and failure to promote long-lasting immunological T cell memory. Activating costimulatory pathways to induce stronger T cell activation may improve the efficacy of checkpoint inhibition and lead to durable antitumor responses. We performed single-cell RNA sequencing of more than 2000 tumor-infiltrating CD8+T cells in mice receiving both PD-1 and GITR (glucocorticoid-induced tumor necrosis factor receptor–related protein) antibodies and found that this combination synergistically enhanced the effector function of expanded CD8+T cells by restoring the balance of key homeostatic regulators CD226 and T cell immunoreceptor with Ig and ITIM domains (TIGIT), leading to a robust survival benefit. Combination therapy decreased CD8+T cell dysfunction and induced a highly proliferative precursor effector memory T cell phenotype in a CD226-dependent manner. PD-1 inhibition rescued CD226 activity by preventing PD-1–Src homology region 2 (SHP2) dephosphophorylation of the CD226 intracellular domain, whereas GITR agonism decreased TIGIT expression. Unmasking the molecular pathways driving durable antitumor responses will be essential to the development of rational approaches to optimizing cancer immunotherapy.

Abstract B077: Signatures of T-cell dysfunction and exclusion predict cancer immunotherapy response

2019 ◽  
Author(s):  
Peng Jiang ◽  
Shengqing Gu ◽  
Deng Pan ◽  
Jingxin Fu ◽  
Avinash Sahu ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Immunotherapy ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

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 Immune-checkpoint inhibitors for combating T-cell dysfunction in cancer

2018 ◽  
Vol Volume 11 ◽  
pp. 6505-6524 ◽  
Author(s):  
Ewelina Grywalska ◽  
Marcin Pasiarski ◽  
Stanisław Góźdź ◽  
Jacek Roliński
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

scholarly journals Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response

2018 ◽  
Vol 24 (10) ◽  
pp. 1550-1558 ◽  
Author(s):  
Peng Jiang ◽  
Shengqing Gu ◽  
Deng Pan ◽  
Jingxin Fu ◽  
Avinash Sahu ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Immunotherapy ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

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 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.

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