Adoptive transfer of gene-engineered CD4+ helper T cells induces potent primary and secondary tumor rejection

Blood ◽  
2005 ◽  
Vol 106 (9) ◽  
pp. 2995-3003 ◽  
Author(s):  
Maria Moeller ◽  
Nicole M. Haynes ◽  
Michael H. Kershaw ◽  
Jacob T. Jackson ◽  
Michele W. L. Teng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Adoptive Transfer ◽  
Cd4 T Cells ◽  
Therapeutic Potential ◽  
Lung Metastases ◽  
Tumor Rejection ◽  
Specific Gene ◽  
Transfer Strategies

AbstractBecause CD4+ T cells play a key role in aiding cellular immune responses, we wanted to assess whether increasing numbers of gene-engineered antigen-restricted CD4+ T cells could enhance an antitumor response mediated by similarly gene-engineered CD8+ T cells. In this study, we have used retroviral transduction to generate erbB2-reactive mouse T-cell populations composed of various proportions of CD4+ and CD8+ cells and then determined the antitumor reactivity of these mixtures. Gene-modified CD4+ and CD8+ T cells were shown to specifically secrete Tc1 (T cytotoxic-1) or Tc2 cytokines, proliferate, and lyse erbB2+ tumor targets following antigen ligation in vitro. In adoptive transfer experiments using severe combined immunodeficient (scid) mice, we demonstrated that injection of equivalent numbers of antigenspecific engineered CD8+ and CD4+ T cells led to significant improvement in survival of mice bearing established lung metastases compared with transfer of unfractionated (largely CD8+) engineered T cells. Transferred CD4+ T cells had to be antigen-specific (not just activated) and secrete interferon γ (IFN-γ) to potentiate the antitumor effect. Importantly, antitumor responses in these mice correlated with localization and persistence of geneengineered T cells at the tumor site. Strikingly, mice that survived primary tumor challenge could reject a subsequent rechallenge. Overall, this study has highlighted the therapeutic potential of using combined transfer of antigen-specific gene-modified CD8+ and CD4+ T cells to significantly enhance T-cell adoptive transfer strategies for cancer therapy.

scholarly journals Expansion of Simian Immunodeficiency Virus (SIV)-Specific CD8 T Cell Lines from SIV-Naive Mauritian Cynomolgus Macaques for Adoptive Transfer

2015 ◽  
Vol 89 (19) ◽  
pp. 9748-9757 ◽  
Author(s):  
Mariel S. Mohns ◽  
Justin M. Greene ◽  
Brian T. Cain ◽  
Ngoc H. Pham ◽  
Emma Gostick ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Cell Lines ◽  
Cd8 T Cells ◽  
Adoptive Transfer ◽  
Cd8 T Cell ◽  
Immunodeficiency Virus ◽  
Cynomolgus Macaques ◽  
Transfer Strategies

ABSTRACTCD8 T cells play a crucial role in the control of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). However, the specific qualities and characteristics of an effective CD8 T cell response remain unclear. Although targeting breadth, cross-reactivity, polyfunctionality, avidity, and specificity are correlated with HIV control, further investigation is needed to determine the precise contributions of these various attributes to CD8 T cell efficacy. We developed protocols for isolating and expanding SIV-specific CD8 T cells from SIV-naive Mauritian cynomolgus macaques (MCM). These cells exhibited an effector memory phenotype, produced cytokines in response to cognate antigen, and suppressed viral replicationin vitro. We further cultured cell lines specific for four SIV-derived epitopes, Nef103–111RM9, Gag389–394GW9, Env338–346RF9, and Nef254–262LT9. These cell lines were up to 94.4% pure, as determined by major histocompatibility complex (MHC) tetramer analysis. After autologous transfer into two MCM recipients, expanded CD8 T cells persisted in peripheral blood and lung tissue for at least 24 weeks and trafficked to multiple extralymphoid tissues. However, these cells did not impact the acute-phase SIV load after challenge compared to historic controls. The expansion and autologous transfer of SIV-specific T cells into naive animals provide a unique model for exploring cellular immunity and the control of SIV infection and facilitate a systematic evaluation of therapeutic adoptive transfer strategies for eradication of the latent reservoir.IMPORTANCECD8 T cells play a crucial role in the control of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). Autologous adoptive transfer studies followed by SIV challenge may help define the critical elements of an effective T cell response to HIV and SIV infection. We developed protocols for isolating and expanding SIV-specific CD8 T cells from SIV-naive Mauritian cynomolgus macaques. This is an important first step toward the development of autologous transfer strategies to explore cellular immunity and potential therapeutic applications in the SIV model.

scholarly journals 519 Diacylglycerol kinase ζ limits IL-2-dependent control of PD-1 expression in tumor-infiltrating T lymphocytes

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A555-A555
Author(s):  
Javier Arranz-Nicolas ◽  
Cristina Rodríguez-Rodríguez ◽  
Rosa Liébana ◽  
Judith Leitner ◽  
Antonia Ávila-Flores ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Line ◽  
Cd8 T Cells ◽  
Therapeutic Potential ◽  
Cd8 T Cell ◽  
Tumor Rejection ◽  
In Vivo Growth ◽  
The Impact

BackgroundTumors evade T cell responses targeting them through the upregulation of tolerance-inducing mechanisms. One of the best characterized is that of PD-1/PD-1L engagement, that in healthy CD8+ T cells limits cytotoxic responses against self-antigens and that tumors employ to neutralize T cell attack. Antibody-based therapies aimed to block the PD-1/PD-1L axis have rendered notable results, but most patients eventually develop resistance. This failure is attributed to CD8+ T cells achieving an exhausted phenotype where recovery is hardly feasible. The dysfunctional phenotype of tumor-infiltrating T cells is largely triggered by the unbalance of diacylglycerol (DAG)- and Ca2+-regulated signals that results in alteration of the transcriptional T cell program. DAG kinase (DGK) ζ-dependent DAG consumption contributes to hypofunctional T cell states while DGKζ deficiency facilitates tumor rejection in mice without apparent adverse autoimmune effects. In spite of its therapeutic potential, little is known about DGKζ function in human T cells and there are not isoform-specific inhibitors targeting this DGK isoform.MethodsHere we used of a human triple parameter reporter (TPR) cell line to examine the consequences of DGKζ depletion in the transcriptional restriction imposed by PD-1 ligation. We also investigated the effect of DGKζ deficiency in the expression dynamics of PD-1, as well as the impact of the absence of this DGK isoform in the in vivo growth of a MC38 adenocarcinoma cell line.ResultsWe demonstrate that DGKζ depletion enhances DAG-regulated transcriptional programs, favoring IL-2 production and limiting PD-1 expression. Diminished PD-1 expression and enhanced expansion of cytotoxic CD8+ T cell populations is also observed even in the context of immunosuppressive milieus and correlates with the failure of MC38 adenocarcinoma cells to form tumors in DGKζ-deficient mice.ConclusionsOur results suggest the relevance of DGKζ as a therapeutic target on its own as well as a biomarker of CD8+ T cell dysfunctional states.

Adoptive Transfer of T Cell Help Breaks Tolerance in Endogenous, Tumor-Specific CD8+ T Cells Responding to a Growing Tumor.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3056-3056
Author(s):  
Jie Wang ◽  
Maryam Aalamian ◽  
Sanju Jalla ◽  
Leo Luznik ◽  
Ephraim J. Fuchs
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Adoptive Transfer ◽  
Cd4 T Cells ◽  
Tumor Vaccine ◽  
Graft Versus Host Reaction ◽  
Vaccine Administration ◽  
T Cell Help

Abstract Patients who reject allogeneic blood or marrow grafts after non-myeloablative conditioning sometimes develop delayed or sustained clinical disease responses, raising the possibility that a transient graft-versus-host reaction rekindles dormant anti-tumor immunity by recipient T cells. More specifically, we postulate that endogenous tumor-specific CD8+ T cells are not irreversibly tolerant of a growing tumor, and can be activated to effector function by tumor antigen recognition in the presence of adoptively transferred CD4+ T cell help. We have tested this hypothesis by examining the response of influenza hemagglutinin (HA)-specific “endogenous” CD8+ T cells in HA-tumor-bearing mice treated with cyclophosphamide (Cy) and adoptive transfer of allogeneic or tumor-specific CD4+ T cells, with or without concomitant tumor vaccine administration. In these models, this combination therapy induced the clonal expansion of endogenous, tumor-specific CD8+ T cells, their secretion of interferon gamma, and in vivo cytolytic activity against HA-expressing cells. In separate experiments, adoptively transferred, major histocompatibility complex-mismatched CD4+ T cells induced the activation of recipient, CD11c+ dendritic cells, as demonstrated by enhanced expression of the costimulatory molecules CD80 and CD86. The administration of Cy followed by infusion of allogeneic T cells, with or without tumor vaccine administration, also induced regression of B cell leukemia/lymphoma or established prostate cancer. These results highlight the potential cooperation of donor CD4+ T cells and recipient CD8+ T cells in transient or stable mixed hematopoietic chimeras, and open new avenues for the immunotherapy of cancer in the clinic.

scholarly journals Reduced immune-regulatory molecule expression on human colonic memory CD4 T cells in older adults

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Stephanie M. Dillon ◽  
Tezha A. Thompson ◽  
Allison J. Christians ◽  
Martin D. McCarter ◽  
Cara C. Wilson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Older Persons ◽  
Age Groups ◽  
T Cell Immunity ◽  
Cd4 T Cell ◽  
Cell Immunity ◽  
Memory Cd4 T Cells

Abstract Background The etiology of the low-level chronic inflammatory state associated with aging is likely multifactorial, but a number of animal and human studies have implicated a functional decline of the gastrointestinal immune system as a potential driver. Gut tissue-resident memory T cells play critical roles in mediating protective immunity and in maintaining gut homeostasis, yet few studies have investigated the effect of aging on human gut T cell immunity. To determine if aging impacted CD4 T cell immunity in the human large intestine, we utilized multi-color flow cytometry to measure colonic lamina propria (LP) CD4 T cell frequencies and immune-modulatory marker expression in younger (mean ± SEM: 38 ± 1.5 yrs) and older (77 ± 1.6 yrs) adults. To determine cellular specificity, we evaluated colon LP CD8 T cell frequency and phenotype in the same donors. To probe tissue specificity, we evaluated the same panel of markers in peripheral blood (PB) CD4 T cells in a separate cohort of similarly aged persons. Results Frequencies of colonic CD4 T cells as a fraction of total LP mononuclear cells were higher in older persons whereas absolute numbers of colonic LP CD4 T cells per gram of tissue were similar in both age groups. LP CD4 T cells from older versus younger persons exhibited reduced CTLA-4, PD-1 and Ki67 expression. Levels of Bcl-2, CD57, CD25 and percentages of activated CD38+HLA-DR+ CD4 T cells were similar in both age groups. In memory PB CD4 T cells, older age was only associated with increased CD57 expression. Significant age effects for LP CD8 T cells were only observed for CTLA-4 expression, with lower levels of expression observed on cells from older adults. Conclusions Greater age was associated with reduced expression of the co-inhibitory receptors CTLA-4 and PD-1 on LP CD4 T cells. Colonic LP CD8 T cells from older persons also displayed reduced CTLA-4 expression. These age-associated profiles were not observed in older PB memory CD4 T cells. The decline in co-inhibitory receptor expression on colonic LP T cells may contribute to local and systemic inflammation via a reduced ability to limit ongoing T cell responses to enteric microbial challenge.

scholarly journals Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates

2008 ◽  
Vol 118 (1) ◽  
pp. 294-305 ◽  
Author(s):  
Carolina Berger ◽  
Michael C. Jensen ◽  
Peter M. Lansdorp ◽  
Mike Gough ◽  
Carole Elliott ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Adoptive Transfer ◽  
Central Memory ◽  
T Cell Memory ◽  
Memory Cells ◽  
Cell Memory ◽  
Central Memory Cells

scholarly journals 739 Intratumor childhood vaccine-specific CD4+ T cell recall helps antitumor CD8 T cells

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A770-A770
Author(s):  
Michael Brown ◽  
Zachary McKay ◽  
Yuanfan Yang ◽  
Darell Bigner ◽  
Smita Nair ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Replication ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Antitumor Efficacy ◽  
Polio Vaccine ◽  
Recall Antigen ◽  
Childhood Vaccine

BackgroundPVSRIPO, a recombinant poliovirus derived from the live-attenuated Sabin oral polio vaccine strain, is being tested in multi-institutional phase II clinical trials for recurrent glioblastoma (NCT04479241) and unresectable, PD-1 refractory melanoma (NCT04577807) in combination with PD1 blockade. PVSRIPO capsid is identical to the Sabin vaccine strain and >99% identical to the inactivated Polio vaccine (IPOL, Salk), against which public health mandated childhood vaccination is near universal. In non-vaccinated mice, PVSRIPO mediates antitumor efficacy in a replication-dependent manner via engaging innate inflammation and antitumor T cells. Accordingly, it is anticipated that pre-existing immunity to PVSRIPO impedes antitumor therapy. However, recent evidence indicates that immunological 'recall', or reactivation of memory T cells, may mediate anti-tumor effects.MethodsThe impact of prior polio vs control (KLH) vaccination on intratumor viral replication, tumor inflammation, and overall tumor growth after intratumor PVSRIPO therapy was assessed in murine tumor models. The role of polio capsid and tetanus recall antigens in mediating intratumor inflammation and antitumor efficacy was similarly studied in mice non-permissive to PVSRIPO infection. To mechanistically define antitumor effects of polio recall, B cell and CD8 T cell knockout mice were used, in addition to adoptive transfer of CD4+ T cells from vaccinated mice. Intratumor polio or tetanus recall antigen therapy was performed after OT-I transfer (OVA-specific T cells) in the B16-OVA melanoma model to gauge antitumor T cell activity. Lastly, the inflammatory effects of polio and tetanus antigens was tested in human peripheral blood mononuclear cells (PBMCs).ResultsDespite curtailing intratumor viral replication, prior polio vaccination in mice potentiated subsequent antitumor efficacy of PVSRIPO. Intratumor recall responses induced by polio and tetanus antigens also delayed tumor growth. Recall antigen therapy was associated with marked intratumor influx of eosinophils, conventional CD4+ T cells, and increased expression of IFN-g, TNF, and Granzyme B in tumor infiltrating T cells. The antitumor efficacy of polio recall antigen was mediated by CD4+ T cells, partially depended upon CD8+ T cells, and was impaired by B cells. Both polio and tetanus recall antigen therapy bolstered the antitumor function of tumor-specific OT-I CD8+ T cells. Polio and tetanus antigens induced CXCL10 and type I/II/III IFNs in PBMCs in vitro.ConclusionsChildhood vaccine-specific CD4+ T cells hold cancer immunotherapy potential. In the context of PVSRIPO therapy, antitumor and inflammatory effects of polio vaccine-specific CD4+ T cell recall supersedes inhibitory effects of attenuated intratumor viral replication, and represents a novel mechanism of action.Ethics ApprovalThe animal work described in this study was approved by the Duke University IACUC.

scholarly journals Human CD4+ T cells specific for dominant epitopes of SARS-CoV-2 Spike and Nucleocapsid proteins with therapeutic potential

2021 ◽  
Author(s):  
Johan Verhagen ◽  
Edith Van der Meijden ◽  
Vanessa Lang ◽  
Andreas Kremer ◽  
Simon Völkl ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cd4 T Cells ◽  
Cellular Therapy ◽  
Therapeutic Potential ◽  
Cell Receptor ◽  
Haematopoietic Stem Cell ◽  
T Cell Therapy ◽  
Immunological Protection

Since December 2019, Coronavirus disease-19 (COVID-19) has spread rapidly across the world, leading to a global effort to develop vaccines and treatments. Despite extensive progress, there remains a need for treatments to bolster the immune responses in infected immunocompromised individuals, such as cancer patients who recently underwent a haematopoietic stem cell transplantation. Immunological protection against COVID-19 is mediated by both short-lived neutralising antibodies and long-lasting virus-reactive T cells. Therefore, we propose that T cell therapy may augment efficacy of current treatments. For the greatest efficacy with minimal adverse effects, it is important that any cellular therapy is designed to be as specific and directed as possible. Here, we identify T cells from COVID-19 patients with a potentially protective response to two major antigens of the SARS-CoV-2 virus, Spike and Nucleocapsid protein. By generating clones of highly virus-reactive CD4+ T cells, we were able to confirm a set of 9 immunodominant epitopes and characterise T cell responses against these. Accordingly, the sensitivity of T cell clones for their specific epitope, as well as the extent and focus of their cytokine response was examined. Moreover, by using an advanced T cell receptor (TCR) sequencing approach, we determined the paired TCR sequences of clones of interest. While these data on a limited population require further expansion for universal application, the results presented here form a crucial first step towards TCR-transgenic CD4+ T cell therapy of COVID-19.

scholarly journals Donor Lymphocyte Infusions Correct Deficiency of Naive T Cells and Improve T-Cell Competence after Allogeneic Haematopoietic Stem Cell Transplantation with Lymphocyte Depletion

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2233-2233
Author(s):  
Monera Al Rukhayes ◽  
Victoria T Potter ◽  
Pilar Perez-Abellan ◽  
Jesus Feliu ◽  
Lajos Floro ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Healthy Volunteers ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Haematopoietic Stem Cell ◽  
Naive T Cells ◽  
Lymphocyte Depletion ◽  
Naïve T Cells ◽  
Repertoire Diversity

Abstract Lymphocyte-depletion effectively reduces risk of graft versus host disease (GvHD) after allogeneic haematopoietic stem cell transplantation (allo-HSCT), but risk of infections and malignant disease relapse remains high. We have previously reported that pre-emptive donor lymphocyte infusions (pDLI) given to patients after allo-HSCT for myeloid malignancies to reverse falling donor T-cell chimerism improve overall and relapse-free survival. GvHD rates after pDLI were not high and grade rarely severe. To investigate the basis for better outcome after pDLI, we have assessed recovery of lymphocyte subsets, T-cell receptor (TCR) diversity and T-cell functional competence after allo-HSCT with fludarabine and busulphan in cohorts of 59 patients (median age 59) given alemtuzumab for lymphocyte-depletion and 34 patients (median age 58) given anti-thymocyte globulin (ATG). Lymphocytes were significantly less depleted with ATG compared to alemtuzumab (Day 30: Median 3.9 x 108/liter versus 2.3x108/liter, P=0.03) but numbers for both ATG and alemtuzumab remained significantly below the normal range (median 2.34x109/liter for 11 aged-matched healthy volunteers) for at least one year (Day 360 P<0.005: Median 8.35 x 108/liter after ATG; median 1.04 x 109/liter after alemtuzumab). Lymphocyte subset composition was similar after ATG or alemtuzumab, and abnormal. Notable, the T-cell population comprised only memory and effector T cells early after HSCT. These cells expressed significantly higher levels of Ki67 than T cells from healthy volunteers (Day 30 P<0.005: Median CD4 T cells 41.3% Ki67+ after ATG, 66% after alemtuzumab compared to 2.51% for healthy volunteers; median CD8 T cells 18.5% Ki67+ after ATG, 50.8% after alemtuzumab compared to 2.58% for healthy volunteers). This marker is indicative of homeostatic proliferation likely driven by increased levels of IL7 and IL15 detected in the serum of patients early after HSCT compared to healthy volunteers (Day 30 P=0.066 and P<0.005 respectively). Higher frequency of T cells expressing the proliferation marker in patients treated with alemtuzumab was associated with high frequencies of T cells expressing the PD1 marker, indicative of exhaustion (Day 30 P<0.005: Median CD4 T cells 84.0% PD1+ after alemtuzumab compared to 6.35% for healthy volunteers; median CD8 T cells 49.1% PD1+ after alemtuzumab compared to 12.3% for healthy volunteers). Expression of PD1 by T cells was near normal in patients treated with ATG. Naïve T cells were typically absent for at least six months after HSCT following lymphocyte depletion with ATG or alemtuzumab, and any subsequent recovery was poor. In contrast, the naïve T-cell population increased rapidly in patients after pDLI (n=18). Six of these patients received pDLI early after HSCT (at 3-5 months) and naïve T-cell recovery was significantly enhanced at six months compared to patients that did not receive pDLI (Day 180 P<0.005: Median 19.25% naïve CD4 T cells compared to 1.36%; median 23.5% naïve CD8 T cells compared to 3.48%). Naïve T cells are the main source of repertoire diversity and responsible for responses to antigens not previously encountered. Analysis of the TCR β chain repertoire of five patients by deep sequencing revealed that pDLI boosts repertoire diversity. For example, unique TCR β chain sequences increased 31-fold in 150 days after pDLI compared to a 2-fold increase during a similar period for another patient that did not receive DLI. Furthermore, instances of emergence of public clonotypes specific for CMV or EBV that were not detected before DLI were seen in virus-positive patients whose donors were virus-negative. Emergence and rapid expansion of donor-derived clonotypes to frequencies up to 6.75% suggests that naïve T cells present in the DLI had been primed upon encounter with virus in the patient. In vitro stimulation with overlapping 15-mer peptide libraries for CMV antigens and EBV antigens followed by assessment of activation marker expression and interferon-γ, MIP-1β, and TNF-α production showed that virus-specific T-cell responses increased in magnitude and poly-functionality after DLI. These findings show that DLI replenishes naïve T cells and restores ability to respond to viral antigens previously unseen. By inference, this may extend to leukaemia antigens and underlie the reduced rate of malignant disease relapse seen in patients given pDLI. Disclosures No relevant conflicts of interest to declare.

scholarly journals Transcription factor Etv6 regulates functional differentiation of cross-presenting classical dendritic cells

2018 ◽  
Vol 215 (9) ◽  
pp. 2265-2278 ◽  
Author(s):  
Colleen M. Lau ◽  
Ioanna Tiniakou ◽  
Oriana A. Perez ◽  
Margaret E. Kirkling ◽  
George S. Yap ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Cd8 T Cells ◽  
Functional Differentiation ◽  
Specific Gene ◽  
Hematopoietic Stem

An IRF8-dependent subset of conventional dendritic cells (cDCs), termed cDC1, effectively cross-primes CD8+ T cells and facilitates tumor-specific T cell responses. Etv6 is an ETS family transcription factor that controls hematopoietic stem and progenitor cell (HSPC) function and thrombopoiesis. We report that like HSPCs, cDCs express Etv6, but not its antagonist, ETS1, whereas interferon-producing plasmacytoid dendritic cells (pDCs) express both factors. Deletion of Etv6 in the bone marrow impaired the generation of cDC1-like cells in vitro and abolished the expression of signature marker CD8α on cDC1 in vivo. Moreover, Etv6-deficient primary cDC1 showed a partial reduction of cDC-specific and cDC1-specific gene expression and chromatin signatures and an aberrant up-regulation of pDC-specific signatures. Accordingly, DC-specific Etv6 deletion impaired CD8+ T cell cross-priming and the generation of tumor antigen–specific CD8+ T cells. Thus, Etv6 optimizes the resolution of cDC1 and pDC expression programs and the functional fitness of cDC1, thereby facilitating T cell cross-priming and tumor-specific responses.

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.

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