scholarly journals Engineering Solutions for Mitigation of Chimeric Antigen Receptor T-Cell Dysfunction

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2326
Author(s):  
Artemis Gavriil ◽  
Marta Barisa ◽  
Emma Halliwell ◽  
John Anderson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Cell Dysfunction ◽  
Car T Cell ◽  
Car T ◽  
T Cell Dysfunction

The clinical successes of chimeric antigen receptor (CAR)-T-cell therapy targeting cell surface antigens in B cell leukaemias and lymphomas has demonstrated the proof of concept that appropriately engineered T-cells have the capacity to destroy advanced cancer with long term remissions ensuing. Nevertheless, it has been significantly more problematic to effect long term clinical benefit in a solid tumour context. A major contributing factor to the clinical failure of CAR-T-cells in solid tumours has been named, almost interchangeably, as T-cell “dysfunction” or “exhaustion”. While unhelpful ambiguity surrounds the term “dysfunction”, “exhaustion” is canonically regarded as a pejorative term for T-cells. Recent understanding of T-cell developmental biology now identifies exhausted cells as vital for effective immune responses in the context of ongoing antigenic challenge. The purpose of this review is to explore the critical stages in the CAR-T-cell life-cycle and their various contributions to T-cell exhaustion. Through an appreciation of the predominant mechanisms of CAR-T-cell exhaustion and resultant dysfunction, we describe a range of engineering approaches to improve CAR-T-cell function.

scholarly journals Chimeric Antigen Receptor T Cell Exhaustion during Treatment for Hematological Malignancies

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Chunyi Shen ◽  
Zhen Zhang ◽  
Yi Zhang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Hematological Malignancies ◽  
Antigen Receptor ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Immunotherapy, especially based on chimeric antigen receptor (CAR) T cells, has achieved prominent success in the treatment of hematological malignancies. However, approximately 30-50% of patients will have disease relapse following remission after receiving CD19-targeting CAR-T cells, with failure of maintaining a long-term effect. Mechanisms underlying CAR-T therapy inefficiency consist of loss or modulation of target antigen and CAR-T cell poor persistence which mostly results from T cell exhaustion. The unique features and restoration strategies of exhausted T cells (Tex) have been well described in solid tumors. However, the overview associated with CAR-T cell exhaustion is relatively rare in hematological malignancies. In this review, we summarize the characteristics, cellular, and molecular mechanisms of Tex cells as well as approaches to reverse CAR-T cell exhaustion in hematological malignancies, providing novel strategies for immunotherapies.

scholarly journals Tim-3 adaptor protein Bat3 is a molecular checkpoint of T cell terminal differentiation and exhaustion

2021 ◽  
Vol 7 (18) ◽  
pp. eabd2710
Author(s):  
Chen Zhu ◽  
Karen O. Dixon ◽  
Kathleen Newcomer ◽  
Guangxiang Gu ◽  
Sheng Xiao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adaptor Protein ◽  
Transcriptional Analysis ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Cell Dysfunction ◽  
Autoreactive T Cell ◽  
Autoimmune Conditions ◽  
T Cell Dysfunction

T cell exhaustion has been associated with poor prognosis in persistent viral infection and cancer. Conversely, in the context of autoimmunity, T cell exhaustion has been favorably correlated with long-term clinical outcome. Understanding the development of exhaustion in autoimmune settings may provide underlying principles that can be exploited to quell autoreactive T cells. Here, we demonstrate that the adaptor molecule Bat3 acts as a molecular checkpoint of T cell exhaustion, with deficiency of Bat3 promoting a profound exhaustion phenotype, suppressing autoreactive T cell–mediated neuroinflammation. Mechanistically, Bat3 acts as a critical mTORC2 inhibitor to suppress Akt function. As a result, Bat3 deficiency leads to increased Akt activity and FoxO1 phosphorylation, indirectly promoting Prdm1 expression. Transcriptional analysis of Bat3−/− T cells revealed up-regulation of dysfunction-associated genes, concomitant with down-regulation of genes associated with T cell effector function, suggesting that absence of Bat3 can trigger T cell dysfunction even under highly proinflammatory autoimmune conditions.

A Failure to Start: Aborted Activation of CAR T Cells in Chronic Lymphocytic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 681-681
Author(s):  
McKensie Collins ◽  
Weimin Kong ◽  
Inyoung Jung ◽  
Meng Wang ◽  
Stefan M Lundh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Research Funding ◽  
Cell Dysfunction ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
T Cell Dysfunction ◽  
Low Levels

Introduction: Chronic Lymphocytic Leukemia (CLL) is a CD19+ B-cell malignancy that accounts for approximately 25% of adult leukemia diagnoses in the developed world. While conventional therapies have some efficacy, there are few curative therapeutic options and many patients ultimately progress to relapsed or refractory disease. CD19-targeting chimeric antigen receptor (CAR) T cell therapy has provided some hope, but induces complete remission in only 26% of patients. This suboptimal response rate is believed to be due to T cell dysfunction and immune-suppression by CLL cells, the mechanisms of which are poorly understood. Results: To understand the causes of CAR T cell dysfunction in CLL we investigated the defects that CLL cells induced in normal donor CD19-targeting CAR T cells. CAR T cells were repeatedly stimulated at 5-day intervals with either primary CLL cells from patients or a CD19-expressing control cell line (aAPC). Repeat stimulation of CAR T cells with aAPCs resulted in 5.36 ± .94 population doublings after three stimulations, whereas CLL cells only evoked 2.39 ± .92 population doublings. We performed phenotyping, proliferation analysis, and cytokine analysis of stimulated CAR T cells. CLL-stimulated T cells appeared un-activated, with low levels of PD-1, LAG3, and TIM3, low levels of cytokine production, and a high proportion of non-cycling cells as measured by Ki67 staining. We first hypothesized that CLL cells induce an altered epigenetic program that prevents effector function and is stabilized by successive stimulations. To test this, we stimulated CAR T cells with CLL cells or aAPCs as indicated in Fig. 1A. CLL-stimulated CAR T cells failed to proliferate or produce cytokines, but subsequent stimulation with aAPCs rescued these functions (Fig. 1B). Further, CLL-stimulated CAR T cells did not differentiate, suggesting that CLL cells do not induce stable defects but rather insufficiently activate CAR T cells (Fig. 1C). These cells also appeared un-activated as indicated by low levels of PD-1 and Ki67. We then used flow cytometry to assess expression of costimulatory and inhibitory molecules on the primary CLL samples. We found that the levels of co-stimulatory and adhesion molecules, namely CD80/CD86 and CD54/CD58 respectively were found at low frequencies, and where present were expressed at low levels. This suggested that one mechanism behind the lack of CAR T cell effector responses may be that a lack of co-stimulation prevents proper CAR T cell targeting of these cells. Towards this, we incubated CLL cells with a murine fibroblast line expressing CD40 ligand for 24 hours with IL-4 to activate the CLL cells. We found that this activation significantly increased expression of CD80, CD86, CD54, and CD58 on the CLL cells. We then used these cells to stimulate CAR T cells in our re-stimulation assay and found that CAR T cells were able to proliferate in response to these activated CLLs (Fig. 1D). In addition, CAR T cells stimulated with activated CLL cells formed more cell-to-cell conjugates than those stimulated with un-activated CLL cells. These data suggest not only that insufficient activation of CAR T cells may be responsible for the poor response rates to CAR T cell therapy in CLL, but also implicate a need for additional co-stimulation in this CAR T cell setting. Another contributing factor may be immune suppression by CLL cells. To determine if CLL cells are immune-suppressive, we used a co-culture assay to stimulate CAR T cells with aAPCs and CLL cells mixed at known ratios. Interestingly, all mixed cultures proliferated similarly, suggesting that CLL cells did not prevent T cell activation in the presence of a strong activation signal. We also found that CLL cells are responsive to IL-2, as addition of this cytokine to culture media prolongs survival of CLL cells out to 10 days depending on the dose. This suggests that CLL cells express a functional IL-2 receptor and may be taking up IL-2 from the culture media, further impairing T cell activation. In support of this, supplementing IL-2 into our CLL/CAR T cell co-cultures rescued T cell proliferative capacity. Taken together, these data suggest that T cell dysfunction in CLL is the result of insufficient activation rather than true functional defects. Disclosures June: Novartis: Research Funding; Tmunity: Other: scientific founder, for which he has founders stock but no income, Patents & Royalties. Melenhorst:National Institutes of Health: Research Funding; Parker Institute for Cancer Immunotherapy: Research Funding; Novartis: Research Funding, Speakers Bureau; IASO Biotherapeutics, Co: Consultancy; Simcere of America, Inc: Consultancy; Shanghai Unicar Therapy, Co: Consultancy; Colorado Clinical and Translational Sciences Institute: Membership on an entity's Board of Directors or advisory committees; Genentech: Speakers Bureau; Stand Up to Cancer: Research Funding; Incyte: Research Funding.

104 BCMA-targeting CAR-T cells expanded in IL-15 have an improved phenotype for therapeutic use compared to those grown in IL-2 or IL-15/IL-7

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A115-A115
Author(s):  
Anthony Battram ◽  
Mireia Bachiller ◽  
Álvaro Urbano-Ispizua ◽  
Beatriz Martin-Antonio
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Cell Dysfunction ◽  
B Cell Maturation ◽  
Car T ◽  
T Cell Dysfunction

BackgroundChimeric antigen receptor-T (CAR-T) cells that target B cell maturation antigen (BCMA-CARs) have emerged as a promising treatment for multiple myeloma (MM). Despite impressive initial responses to BCMA-CAR therapy in clinical trials, relapse is common, signifying a need to improve the in vivo efficacy and persistence of BCMA-CARs.1 The development of unfavourable differentiation or T cell dysfunction, such as exhaustion and senescence, during the ex vivo expansion of the BCMA-CARs could be limiting their therapeutic potential. For CD19-directed CARs, reduced dysfunction and differentiation and improved anti-tumour responses were achieved by expanding the cells with IL-15 instead of IL-2.2 Therefore, in this study, our aim was to determine whether expanding BCMA-CARs with IL-15 or IL-15/IL-7 instead of IL-2 alters their levels of exhaustion, senescence, differentiation and activity.MethodsT cells stimulated with anti-CD3/anti-CD28-coated beads were supplemented with IL-2, IL-15, IL-15 + IL-7 or no cytokine and transduced with ARI2h, a BCMA-CAR with a 4-1BB co-stimulatory domain produced at our institution.3 Expanded BCMA-CARs were analysed by flow cytometry for markers of T cell dysfunction, or challenged with MM cell line ARP-1 and then tested for cytokine production, cytotoxic ability and activation signals.ResultsBCMA-CARs cultured in IL-15 or IL-15/IL-7 expanded similarly to those grown in IL-2, with comparable CAR transduction efficiencies, CD4:CD8 ratios and proliferation rates. BCMA-CARs grown in IL-15 had low expression of exhaustion marker LAG-3 and high expression of the costimulatory molecule CD27, which is important for T cell survival and persistence, when compared to BCMA-CARs cultured in IL-2. Moreover, BCMA-CARs grown solely in IL-15 were less differentiated than those supplemented with IL-7, and had higher expression of stem cell memory marker CXCR3 within the naïve population than those expanded with IL-2. When challenged with MM cell line ARP-1, IL-15-grown BCMA-CARs upregulated activation marker CD69, exhibited strong cytotoxicity and robust production of IFNγ and IL-2. However, in comparison to BCMA-CARs expanded in IL-2 or IL-15/IL-7, those grown with IL-15 had lower mTORC1 activity and p38 MAPK phosphorylation when activated by ARP-1 cells, suggesting differential regulation of key pathways for T cell metabolism and senescence, respectively.ConclusionsTo summarise, BCMA-CARs expanded with IL-15 alone exhibited the most favourable phenotype for therapeutic use compared those grown with IL-2 or IL-15/IL-7. Future experiments using murine MM models will be critical in understanding the in vivo benefits or drawbacks of culturing BCMA-CARs in IL-15 compared to IL-2 or IL-15/IL-7.Ethics ApprovalResearch involving human material was approved by the Ethical Committee of Clinical Research (Hospital Clinic, Barcelona). Peripheral blood T cells were obtained from healthy donors after informed consent in accordance with the Declaration of Helsinki.ReferencesRoex G, Feys T, Beguin Y, Kerre T, Poiré X, Lewalle P, et al. Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data. Pharmaceutics [Internet]. 2020;12:1–15. Available from: http://www.ncbi.nlm.nih.gov/pubmed/32102267Alizadeh D, Wong RA, Yang X, Wang D, Pecoraro JR, Kuo CF, et al. IL15 enhances CAR-T cell antitumor activity by reducing mTORC1 activity and preserving their stem cell memory phenotype. Cancer Immunol Res 2019;7:759–72.Perez-Amill L, Suñe G, Antoñana-Vildosola A, Castella M, Najjar A, Bonet J, et al. Preclinical development of a humanized chimeric antigen receptor against B cell maturation antigen for multiple myeloma. Haematologica [Internet]. 2020; Available from: http://www.ncbi.nlm.nih.gov/pubmed/31919085

scholarly journals 493 Tired and hungry: a potential role for CD47 in T cell exhaustion

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A529-A529
Author(s):  
Levi Mangarin ◽  
Cailian Liu ◽  
Roberta Zappasodi ◽  
Pamela Holland ◽  
Jedd Wolchok ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Effector Function ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Cell Dysfunction ◽  
Melanoma Model ◽  
T Cell Dysfunction ◽  
Melanoma Patients

BackgroundMultiple suppressive mechanisms within the tumor microenvironment are capable of blunting anti-tumor T cell responses, including the engagement of inhibitory receptors expressed in tumor-associated, exhausted CD8+ T cells, such as programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), 2B4 (also known as CD244), and T cell immunoreceptor with Ig and ITIM domains (TIGIT).1 2 While immune checkpoint blockade therapies aimed at reinvigorating T cell effector function have demonstrated their clinical effectiveness,3 4 not all patients demonstrate long-term disease control.5 The refractory nature of terminally differentiated, exhausted CD8+ T cells to be reinvigorated by PD-1 blockade is one potential cause.6–8 This limitation warrants the need to explore modulatory pathways that potentially program T cells toward exhaustion.MethodsSingle cell-RNA sequencing (scRNA-seq) data derived from the tumor-infiltrating lymphocytes (TILs) of melanoma patients9 were used for transcriptomic analysis and flow cytometry results were used to quantify protein levels in TILs. Murine B16-F10 (B16) melanoma model was used for both in vitro and in vivo studies. TCR-transgenic Pmel-1 and OT-1 transgenic mice, as well as CD47-/- (knockout, KO) mice were purchased from the Jackson Laboratory to generate CD47+/+ (wild-type, WT), CD47± (heterozygote, HET) mice with Pmel-1 or OT-1 background. For T cell co-transfer studies, Rag-deficient mice or C57BL/6j mice with sub-lethal irradiation (600cGy) were used as recipients. Naïve TCR-transgenic CD47-WT and CD47-HET CD8+ T cells were labelled, mixed in a 1:1 ratio for co-transfer experiments.ResultsFlow cytometry analysis of human melanoma TILs found a strong upregulation of CD47 expression in tumor-associated, exhausted CD8+ T cells. We confirmed that CD47 transcription is significantly elevated among CD8+ T cells with a phenotype consistent with exhaustion using scRNA-seq results of TILs derived from melanoma patients.9 Our study in murine B16 melanoma model confirms our finding in melanoma patients. To specifically address the role of CD47 in anti-tumor CD8 effector function, we conducted T cell co-transfer studies and found that CD8+ T cells with lower copy number of CD47 (CD47-HET) significantly outnumber the co-transferred CD47-WT CD8+ T cells within the tumor, exhibiting an enhanced effector function and less exhausted phenotype. Our study demonstrates a potentially novel role for CD47 in mediating CD8+ T cell exhaustion.ConclusionsCD47 expression in CD8+ T cells programs T cells toward exhaustion.Ethics ApprovalAll mice were maintained in microisolator cages and treated in accordance with the NIH and American Association of Laboratory Animal Care regulations. All mouse procedures and experiments for this study were approved by the MSKCC Institutional Animal Care and Use Committee (IACUC).ReferencesWherry EJ and M Kurachi. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol 2015;15(8): p. 486–99.Thommen DS and Schumacher TN. T Cell Dysfunction in Cancer. Cancer Cell 2018;33(4): p. 547–562.Ribas A and Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 2018. 359(6382): p. 1350–1355.Sharma P and Allison JP. The future of immune checkpoint therapy. Science 2015; 48(6230): p. 56–61.Sharma P, et al. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 2017. 168(4): p. 707–723.Schietinger, A., et al., Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity 2016;45(2): p. 389–401.Pauken KE, et al., Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 2016;354(6316): p. 1160–1165.Philip M, et al., Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature 2017;545(7655): p. 452–456.Sade-Feldman M, et al., Defining T Cell States associated with response to checkpoint immunotherapy in melanoma. Cell 2018;175(4): p. 998–1013e20.

scholarly journals Blimp-1–mediated CD4 T cell exhaustion causes CD8 T cell dysfunction during chronic toxoplasmosis

2016 ◽  
Vol 213 (9) ◽  
pp. 1799-1818 ◽  
Author(s):  
SuJin Hwang ◽  
Dustin A. Cobb ◽  
Rajarshi Bhadra ◽  
Ben Youngblood ◽  
Imtiaz A. Khan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Critical Role ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

CD8, but not CD4, T cells are considered critical for control of chronic toxoplasmosis. Although CD8 exhaustion has been previously reported in Toxoplasma encephalitis (TE)–susceptible model, our current work demonstrates that CD4 not only become exhausted during chronic toxoplasmosis but this dysfunction is more pronounced than CD8 T cells. Exhausted CD4 population expressed elevated levels of multiple inhibitory receptors concomitant with the reduced functionality and up-regulation of Blimp-1, a transcription factor. Our data demonstrates for the first time that Blimp-1 is a critical regulator for CD4 T cell exhaustion especially in the CD4 central memory cell subset. Using a tamoxifen-dependent conditional Blimp-1 knockout mixed bone marrow chimera as well as an adoptive transfer approach, we show that CD4 T cell–intrinsic deletion of Blimp-1 reversed CD8 T cell dysfunction and resulted in improved pathogen control. To the best of our knowledge, this is a novel finding, which demonstrates the role of Blimp-1 as a critical regulator of CD4 dysfunction and links it to the CD8 T cell dysfunctionality observed in infected mice. The critical role of CD4-intrinsic Blimp-1 expression in mediating CD4 and CD8 T cell exhaustion may provide a rational basis for designing novel therapeutic approaches.

scholarly journals TOX defines the degree of CD8+ T cell dysfunction in distinct phases of chronic HBV infection

Gut ◽  
2020 ◽  
pp. gutjnl-2020-322404
Author(s):  
Kathrin Heim ◽  
Benedikt Binder ◽  
Sagar ◽  
Dominik Wieland ◽  
Nina Hensel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Hbv Infection ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Cell Dysfunction ◽  
Chronic Hepatitis B Virus ◽  
T Cell Dysfunction

ObjectiveChronic hepatitis B virus (HBV) infection is characterised by HBV-specific CD8+ T cell dysfunction that has been linked to Tcell exhaustion, a distinct differentiation programme associated with persisting antigen recognition. Recently, Thymocyte Selection-Associated High Mobility Group Box (TOX) was identified as master regulator of CD8+ T cell exhaustion. Here, we addressed the role of TOX in HBV-specific CD8+ T cell dysfunction associated with different clinical phases of infection.DesignWe investigated TOX expression in HBV-specific CD8+ T cells from 53 HLA-A*01:01, HLA-A*11:01 and HLA-A*02:01 positive patients from different HBV infection phases and compared it to hepatitis C virus (HCV)-specific, cytomegalovirus (CMV)-specific, Epstein-Barr virus (EBV)-specific and influenza virus (FLU)-specific CD8+ T cells. Phenotypic and functional analyses of virus-specific CD8+ T cells were performed after peptide-loaded tetramer-enrichment and peptide-specific expansion.ResultsOur results show that TOX expression in HBV-specific CD8+ T cells is linked to chronic antigen stimulation, correlates with viral load and is associated with phenotypic and functional characteristics of T-cell exhaustion. In contrast, similar TOX expression in EBV-specific and CMV-specific CD8+ T cells is not linked to T-cell dysfunction suggesting different underlying programmes. TOX expression in HBV-specific CD8+ T cells is also affected by targeted antigens, for example, core versus polymerase. In HBV-specific CD8+ T cells, TOX expression is maintained after spontaneous or therapy-mediated viral control in chronic but not self-limiting acute HBV infection indicating a permanent molecular imprint after chronic but not temporary stimulation.ConclusionOur data highlight TOX as biomarker specific for dysfunctional virus-specific CD8+ T cells in the context of an actively persisting infection.

scholarly journals Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells

2015 ◽  
Vol 212 (7) ◽  
pp. 1125-1137 ◽  
Author(s):  
Pamela M. Odorizzi ◽  
Kristen E. Pauken ◽  
Michael A. Paley ◽  
Arlene Sharpe ◽  
E. John Wherry
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Lymphocytic Choriomeningitis ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Cell Dysfunction ◽  
T Cell Dysfunction ◽  
T Cell Survival

Programmed Death-1 (PD-1) has received considerable attention as a key regulator of CD8+ T cell exhaustion during chronic infection and cancer because blockade of this pathway partially reverses T cell dysfunction. Although the PD-1 pathway is critical in regulating established “exhausted” CD8+ T cells (TEX cells), it is unclear whether PD-1 directly causes T cell exhaustion. We show that PD-1 is not required for the induction of exhaustion in mice with chronic lymphocytic choriomeningitis virus (LCMV) infection. In fact, some aspects of exhaustion are more severe with genetic deletion of PD-1 from the onset of infection. Increased proliferation between days 8 and 14 postinfection is associated with subsequent decreased CD8+ T cell survival and disruption of a critical proliferative hierarchy necessary to maintain exhausted populations long term. Ultimately, the absence of PD-1 leads to the accumulation of more cytotoxic, but terminally differentiated, CD8+ TEX cells. These results demonstrate that CD8+ T cell exhaustion can occur in the absence of PD-1. They also highlight a novel role for PD-1 in preserving TEX cell populations from overstimulation, excessive proliferation, and terminal differentiation.

scholarly journals Meta-analysis of exhausted CD8+ T cells from Homo sapiens and Mus musculus provides robust targets for immunotherapy

2021 ◽  
Author(s):  
Lin Zhang ◽  
Yicheng Guo ◽  
Hafumi Nishi
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

T cell exhaustion is a state of T cell dysfunction during chronic infection and cancer. Antibody-targeting immune checkpoint inhibitors to reverse T cell exhaustion is a promising approach for cancer immunotherapy. However, the therapeutic efficacy of known immune checkpoint inhibitors remains low. To expand the potential effective targets to reverse T cell exhaustion, a meta-analysis was performed to integrate seven exhaustion datasets caused by multiple diseases in both humans and mice. In this study, an overlap of 21 upregulated and 37 downregulated genes was identified in human and mouse exhausted CD8+ T cells. These genes were significantly enriched in exhaustion response-related pathways, such as signal transduction, immune system processes, and regulation of cytokine production. Gene expression network analysis revealed that the well-documented exhaustion genes were defined as hub genes in upregulated genes, such as programmed cell death protein 1 and cytotoxic T-lymphocyte associated protein 4. In addition, a weighted gene co-expression analysis identified 175 overlapping genes that were significantly correlated with the exhaustion trait in both humans and mice. This study found that nine genes, including thymocyte selection associated high mobility group box and CD200 receptor 1, were significantly upregulated and highly related to T cell exhaustion. These genes should be additional robust targets for immunotherapy and T-cell dysfunction studies.

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