scholarly journals ATPIF1 inactivation promotes antitumor immunity through metabolic reprogramming of CD8+ T cells

2020 ◽  
Author(s):  
Genshen Zhong ◽  
Ying Wang ◽  
Jiaojiao Zhang ◽  
Yichun Wang ◽  
Yuan Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Antitumor Immunity ◽  
Cell Activity ◽  
Tumor Infiltrating Lymphocytes ◽  
Metabolic Reprogramming ◽  
Apoptosis Resistance ◽  
Lewis Lung Cancer ◽  
Cell Immunity

AbstractInduction of CD8+ T cell activity is a promising strategy in the cancer immunotherapy. In this study, we identified ATP synthase inhibitory factor 1 (ATPIF1) as a potential target in the induction of CD8+ T cell immunity against tumor. Inactivation of ATPIF1 gene in mice promoted the antitumor activity of CD8+ T cells leading to suppression of tumor growth of B16 melanoma and Lewis lung cancer. The phenotype was abolished by deletion of CD8+ T cells in the ATPIF1-KO mice. The tumor infiltrating CD8+ T cells exhibited strong activities in the proliferation, effector and memory as revealed by the single cell RNA sequencing results of CD45+ tumor infiltrating lymphocytes (TILs) isolated from the tumors. The CD8+ T cells expressed more antitumor makers in the tumor microenvironment and in coculture with the tumor cells. The cells had a higher level of glycolysis after the T cell receptor-mediated activation as revealed by the targeted metabolomics assay. The cells exhibited an extra activity of oxidative phosphorylation before the activation as indicated by the oxygen consumption rate. The cells gained capacities in the proliferation, apoptosis resistance and mitophagy in the glucose-limiting environment. These data suggest that inhibition of ATPIF1 activity by gene inactivation rewired the energy metabolism of CD8+ T cells to enhance their immune activities to the tumors. ATPIF1 is a potential molecular target in the induction of antitumor immunity through metabolic reprogramming of CD8+ T cells for the cancer immunotherapy.

scholarly journals Amino acids and RagD potentiate mTORC1 activation in CD8+ T cells to confer antitumor immunity

2021 ◽  
Vol 9 (4) ◽  
pp. e002137
Author(s):  
Yiwen Zhang ◽  
Hongrong Hu ◽  
Weiwei Liu ◽  
Shu-Mei Yan ◽  
Yuzhuang Li ◽  
...  
Keyword(s):  
Amino Acids ◽  
T Cells ◽  
Amino Acid ◽  
T Cell ◽  
Antitumor Immunity ◽  
Tumor Infiltrating Lymphocytes ◽  
Human Colon Cancer ◽  
Cell Immunity ◽  
Mtorc1 Signaling

BackgroundIn the tumor microenvironment, tumor cells are able to suppress antitumor immunity by competing for essential nutrients, including amino acids. However, whether amino acid depletion modulates the activity of CD8+ tumor-infiltrating lymphocytes (TILs) is unclear.MethodIn this study, we evaluated the roles of amino acids and the Rag complex in regulating mammalian target of rapamycin complex 1 (mTORC1) signaling in CD8+ TILs.ResultsWe discovered that the Rag complex, particularly RagD, was crucial for CD8+ T-cell antitumor immunity. RagD expression was positively correlated with the antitumor response of CD8+ TILs in both murine syngeneic tumor xenografts and clinical human colon cancer samples. On RagD deficiency, CD8+ T cells were rendered more dysfunctional, as demonstrated by attenuation of mTORC1 signaling and reductions in proliferation and cytokine secretion. Amino acids maintained RagD-mediated mTORC1 translocation to the lysosome, thereby achieving maximal mTORC1 activity in CD8+ T cells. Moreover, the limited T-cell access to leucine (LEU), overshadowed by tumor cell amino acid consumption, led to impaired RagD-dependent mTORC1 activity. Finally, combined with antiprogrammed cell death protein 1 antibody, LEU supplementation improved T-cell immunity in MC38 tumor-bearing mice in vivo.ConclusionOur results revealed that robust signaling of amino acids by RagD and downstream mTORC1 signaling were crucial for T-cell receptor-initiated antitumor immunity. The characterization the role of RagD and LEU in nutrient mTORC1 signaling in TILs might suggest potential therapeutic strategies based on the manipulation of RagD and its upstream pathway.

scholarly journals Alloantigen-activated (AAA) CD4+ T cells reinvigorate host endogenous T cell immunity to eliminate pre-established tumors in mice

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Kazuhiro Mochizuki ◽  
Shogo Kobayashi ◽  
Nobuhisa Takahashi ◽  
Kotaro Sugimoto ◽  
Hideki Sano ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Antitumor Immunity ◽  
Unmet Need ◽  
T Cell Response ◽  
Hematopoietic Stem ◽  
Cell Immunity ◽  
Allogeneic Lymphocytes

Abstract Background Cancer vaccines that induce endogenous antitumor immunity represent an ideal strategy to overcome intractable cancers. However, doing this against a pre-established cancer using autologous immune cells has proven to be challenging. “Allogeneic effects” refers to the induction of an endogenous immune response upon adoptive transfer of allogeneic lymphocytes without utilizing hematopoietic stem cell transplantation. While allogeneic lymphocytes have a potent ability to activate host immunity as a cell adjuvant, novel strategies that can activate endogenous antitumor activity in cancer patients remain an unmet need. In this study, we established a new method to destroy pre-developed tumors and confer potent antitumor immunity in mice using alloantigen-activated CD4+ (named AAA-CD4+) T cells. Methods AAA-CD4+ T cells were generated from CD4+ T cells isolated from BALB/c mice in cultures with dendritic cells (DCs) induced from C57BL/6 (B6) mice. In this culture, allogeneic CD4+ T cells that recognize and react to B6 mouse-derived alloantigens are preferentially activated. These AAA-CD4+ T cells were directly injected into the pre-established melanoma in B6 mice to assess their ability to elicit antitumor immunity in vivo. Results Upon intratumoral injection, these AAA-CD4+ T cells underwent a dramatic expansion in the tumor and secreted high levels of IFN-γ and IL-2. This was accompanied by markedly increased infiltration of host-derived CD8+ T cells, CD4+ T cells, natural killer (NK) cells, DCs, and type-1 like macrophages. Selective depletion of host CD8+ T cells, rather than NK cells, abrogated this therapeutic effect. Thus, intratumoral administration of AAA-CD4+ T cells results in a robust endogenous CD8+ T cell response that destroys pre-established melanoma. This locally induced antitumor immunity elicited systemic protection to eliminate tumors at distal sites, persisted over 6 months in vivo, and protected the animals from tumor re-challenge. Notably, the injected AAA-CD4+ T cells disappeared within 7 days and caused no adverse reactions. Conclusions Our findings indicate that AAA-CD4+ T cells reinvigorate endogenous cytotoxic T cells to eradicate pre-established melanoma and induce long-term protective antitumor immunity. This approach can be immediately applied to patients with advanced melanoma and may have broad implications in the treatment of other types of solid tumors.

scholarly journals Immunotransplantation preferentially expands T-effector cells over T-regulatory cells and cures large lymphoma tumors

Blood ◽  
2009 ◽  
Vol 113 (1) ◽  
pp. 85-94 ◽  
Author(s):  
Joshua D. Brody ◽  
Matthew J. Goldstein ◽  
Debra K. Czerwinski ◽  
Ronald Levy
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Regulatory Cells ◽  
Ex Vivo ◽  
Booster Vaccination ◽  
Tumor Infiltrating Lymphocytes ◽  
Hematopoietic Stem ◽  
T Effector Cells ◽  
Cell Immunity

Abstract Ex vivo–expanded tumor-infiltrating lymphocytes infused into lymphodepleted recipients has clear antitumor efficacy. More practical sources of such antitumor lymphocytes would broaden the application of this approach. Previously, we described an in situ vaccination combining chemotherapy with intratumoral injection of CpG-enriched oligonucleotides, which induced T-cell immunity against established lymphoma. An ongoing clinical trial of this maneuver has demonstrated clinical responses in lymphoma patients. Here, we use this vaccine maneuver to generate immune cells for transfer into irradiated, syngeneic recipients. Transferred tumor-specific T-effector (Teff) cells preferentially expanded, increasing the Teff/T-regulatory (Treg) ratio in these “immunotransplantation” recipients and curing large and metastatic tumors. Donor T cells were necessary for tumor protection, and CD8 T-cell immune responses were enhanced by posttransplantation booster vaccination. Hematopoietic stem cell transplantation is a standard therapy for lymphoma. Therefore, in situ tumor vaccination followed by immunotransplantation of harvested tumor-specific T cells could be directly tested in clinical trials to treat otherwise resistant malignancies.

scholarly journals The GPR171 pathway suppresses T cell activation and limits antitumor immunity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yuki Fujiwara ◽  
Robert J. Torphy ◽  
Yi Sun ◽  
Emily N. Miller ◽  
Felix Ho ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Antitumor Immunity ◽  
Cell Activation ◽  
Cell Receptor ◽  
Immune Checkpoint Blockade ◽  
T Cell Immunity ◽  
Antigen Stimulation ◽  
Cell Immunity

AbstractThe recently identified G-protein-coupled receptor GPR171 and its ligand BigLEN are thought to regulate food uptake and anxiety. Though GPR171 is commonly used as a T cell signature gene in transcriptomic studies, its potential role in T cell immunity has not been explored. Here we show that GPR171 is transcribed in T cells and its protein expression is induced upon antigen stimulation. The neuropeptide ligand BigLEN interacts with GPR171 to suppress T cell receptor-mediated signalling pathways and to inhibit T cell proliferation. Loss of GPR171 in T cells leads to hyperactivity to antigen stimulation and GPR171 knockout mice exhibit enhanced antitumor immunity. Blockade of GPR171 signalling by an antagonist promotes antitumor T cell immunity and improves immune checkpoint blockade therapies. Together, our study identifies the GPR171/BigLEN axis as a T cell checkpoint pathway that can be modulated for cancer immunotherapy.

scholarly journals TGF-β in T Cell Biology: Implications for Cancer Immunotherapy

Cancers ◽  
2018 ◽  
Vol 10 (6) ◽  
pp. 194 ◽  
Author(s):  
Amina Dahmani ◽  
Jean-Sébastien Delisle
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Transforming Growth Factor Beta ◽  
Cell Biology ◽  
Transforming Growth Factor ◽  
Tumor Control ◽  
Neoplastic Progression ◽  
Cell Immunity ◽  
T Cell Biology

Transforming Growth Factor beta (TGF-β) is a pleiotropic cytokine produced in large amounts within cancer microenvironments that will ultimately promote neoplastic progression, notably by suppressing the host’s T-cell immunosurveillance. This effect is mostly due to the well-known inhibitory effect of TGF-β on T cell proliferation, activation, and effector functions. Moreover, TGF-β subverts T cell immunity by favoring regulatory T-cell differentiation, further reinforcing immunosuppression within tumor microenvironments. These findings stimulated the development of many strategies to block TGF-β or its signaling pathways, either as monotherapy or in combination with other therapies, to restore anti-cancer immunity. Paradoxically, recent studies provided evidence that TGF-β can also promote differentiation of certain inflammatory populations of T cells, such as Th17, Th9, and resident-memory T cells (Trm), which have been associated with improved tumor control in several models. Here, we review current advances in our understanding of the many roles of TGF-β in T cell biology in the context of tumor immunity and discuss the possibility to manipulate TGF-β signaling to improve cancer immunotherapy.

scholarly journals NK Cells Help To Induce CD8+-T-Cell Immunity against Toxoplasma gondii in the Absence of CD4+ T Cells

2005 ◽  
Vol 73 (8) ◽  
pp. 4913-4921 ◽  
Author(s):  
Crescent L. Combe ◽  
Tyler J. Curiel ◽  
Magali M. Moretto ◽  
Imtiaz A. Khan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
Nk Cells ◽  
Cell Response ◽  
Nk Cell ◽  
Cell Activity ◽  
T Cell Immunity ◽  
Interleukin 12 ◽  
Cell Immunity

ABSTRACT CD8+ T-cell immunity plays an important role in protection against intracellular infections. Earlier studies have shown that CD4+ T-cell help was needed for launching in vivo CD8+ T-cell activity against these pathogens and tumors. However, recently CD4+ T-cell-independent CD8 responses during several microbial infections including those with Toxoplasma gondii have been described, although the mechanism is not understood. We now demonstrate that, in the absence of CD4+ T cells, T. gondii-infected mice exhibit an extended NK cell response, which is mediated by continued interleukin-12 (IL-12) secretion. This prolonged NK cell response is critical for priming parasite-specific CD8+ T-cell immunity. Depletion of NK cells inhibited the generation of CD8+ T-cell immunity in CD4−/− mice. Similarly neutralization of IL-12 reduces NK cell numbers in infected animals and leads to the down-regulation of CD8+ T-cell immunity against T. gondii. Adoptive transfer of NK cells into the IL-12-depleted animals restored their CD8+ T-cell immune response, and animals exhibited reduced mortality. NK cell gamma interferon was essential for cytotoxic T-lymphocyte priming. Our studies for the first time demonstrate that, in the absence of CD4+ T cells, NK cells can play an important role in induction of primary CD8+ T-cell immunity against an intracellular infection. These observations have therapeutic implications for immunocompromised individuals, including those with human immunodeficiency virus infection.

scholarly journals The future of immunotherapy

2020 ◽  
Author(s):  
Cornelis J M Melief
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Tumor Infiltrating Lymphocytes ◽  
Checkpoint Control ◽  
Checks And Balances ◽  
Drug Conjugates ◽  
Cell Immunity ◽  
Anti Cd20 ◽  
Infiltrating Lymphocytes

Abstract During the last two decades two main schools of modern immunotherapy have come to the forefront. The chimeric anti-CD20 antibody rituximab that was introduced for the treatment of refractory follicular lymphoma in 1998 was one of the first examples of the school of passive immunotherapy. Subsequently major and ever more costly efforts were spent on the development of blockbuster monotherapies including other monoclonal but also bispecific antibodies of highly defined specificity and subclass, antibody-drug-conjugates (ADCs), as well as ex vivo expanded tumor infiltrating lymphocytes, CAR-transduced T cells, and TCR-transduced T cells. On the other hand there is the school that works towards active induction of patient B- or T-cell immunity against antigens of choice, or active tolerance against pathogenic allergens, auto-antigens or allo-antigens. Stradled in between these two approaches is treatment with blockers of T cell checkpoint control, which releases the brakes of T cells that have already responded to antigen. Extensive and detailed insight into the cellular and molecular interactions that regulate specific immune responses is indispensable in order to be able to optimize efficacy and rule out treatment related toxicity. This applies to all types of immunotherapy. Our knowledge of the checks and balances in the immune system is still increasing at an unprecedented pace, fostering ever more effective and specific (combination) immunotherapies and offering a rich harvest of innovative immunotherapies in the years ahead.

scholarly journals Creatine in T Cell Antitumor Immunity and Cancer Immunotherapy

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1633
Author(s):  
Bo Li ◽  
Lili Yang
Keyword(s):  
T Cell ◽  
Cancer Immunotherapy ◽  
Metabolic Regulation ◽  
Antitumor Immunity ◽  
Creatine Supplementation ◽  
Research Field ◽  
Mouse Tumor ◽  
Cell Immunity ◽  
Regulatory Functions ◽  
Mouse Tumor Models

Creatine is a broadly used dietary supplement that has been extensively studied for its benefit on the musculoskeletal system. Yet, there is limited knowledge regarding the metabolic regulation of creatine in cells beyond the muscle. New insights concerning various regulatory functions for creatine in other physiological systems are developing. Here, we highlight the latest advances in understanding creatine regulation of T cell antitumor immunity, a topic that has previously gained little attention in the creatine research field. Creatine has been identified as an important metabolic regulator conserving bioenergy to power CD8 T cell antitumor reactivity in a tumor microenvironment; creatine supplementation has been shown to enhance antitumor T cell immunity in multiple preclinical mouse tumor models and, importantly, to synergize with other cancer immunotherapy modalities, such as the PD-1/PD-L1 blockade therapy, to improve antitumor efficacy. The potential application of creatine supplementation for cancer immunotherapy and the relevant considerations are discussed.

scholarly journals IL-31 induces antitumor immunity in breast carcinoma

2020 ◽  
Vol 8 (2) ◽  
pp. e001010
Author(s):  
Tal Kan ◽  
Erik Feldman ◽  
Michael Timaner ◽  
Ziv Raviv ◽  
Shai Shen-Orr ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Breast Carcinoma ◽  
T Cell Activation ◽  
Antitumor Immunity ◽  
Cell Activity ◽  
Cytotoxic T Cell ◽  
Therapeutic Activity

BackgroundImmunomodulatory agents that induce antitumor immunity have great potential for treatment of cancer. We have previously shown that interleukin (IL)-31, a proinflammatory cytokine from the IL-6 family, acts as an antiangiogenic agent. Here, we characterize the immunomodulatory effect of IL-31 in breast cancer.MethodsIn vivo breast carcinoma models including EMT6 and PyMT cell lines were used to analyze the effect of IL-31 on the composition of various immune cells in the tumor microenvironment using high-throughput flow cytometry. In vitro studies using isolated cytotoxic T cells, CD4+ T cells, myeloid-derived suppressor cells (MDSCs) and macrophages were carried out to study IL-31 immunological activity. The generation of recombinant IL-31 bound to IgG backbone was used to test IL-31 therapeutic activity.ResultsThe growth rate of IL-31-expressing breast carcinomas is decreased in comparison with control tumors due, in part, to antitumor immunomodulation. Specifically, cytotoxic T cell activity is increased, whereas the levels of CD4+ T cells, MDSCs, and tumor-associated macrophages are decreased in IL-31-expressing tumors. These cellular changes are accompanied by a cytokine profile associated with antitumor immunity. In vitro, IL-31 directly inhibits CD4+ Th0 cell proliferation, and the expression of Th2 canonical factors GATA3 and IL-4. It also promotes CD8+ T cell activation through inhibition of MDSC activity and motility. Clinically, in agreement with the mouse data, alterations in immune cell composition in human breast cancer biopsies were found to correlate with high expression of IL-31 receptor A (IL-31Ra) . Furthermore, high coexpression of IL-31Ra, IL-2 and IL-4 in tumors correlates with increased survival. Lastly, to study the therapeutic potential of IL-31, a recombinant murine IL-31 molecule was fused to IgG via a linker region (IL-31-L-IgG). This IL-31-L-IgG therapy demonstrates antitumor therapeutic activity in a murine breast carcinoma model.ConclusionsOur findings demonstrate that IL-31 induces antitumor immunity, highlighting its potential utility as a therapeutic immunomodulatory agent.

JAML promotes CD8 and γδ T cell antitumor immunity and is a novel target for cancer immunotherapy

2021 ◽  
Vol 218 (10) ◽  
Author(s):  
Joseph M. McGraw ◽  
Flavian Thelen ◽  
Eric N. Hampton ◽  
Nelson E. Bruno ◽  
Travis S. Young ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Cancer Immunotherapy ◽  
Antitumor Immunity ◽  
Tumor Infiltrating Lymphocytes ◽  
Tissue Loss ◽  
Mouse Tumor ◽  
Novel Target ◽  
Adenovirus Receptor ◽  
Infiltrating Lymphocytes

T cells are critical mediators of antitumor immunity and a major target for cancer immunotherapy. Antibody blockade of inhibitory receptors such as PD-1 can partially restore the activity of tumor-infiltrating lymphocytes (TILs). However, the activation signals required to promote TIL responses are less well characterized. Here we show that the antitumor activity of CD8 and γδ TIL is supported by interactions between junctional adhesion molecule–like protein (JAML) on T cells and its ligand coxsackie and adenovirus receptor (CXADR) within tumor tissue. Loss of JAML through knockout in mice resulted in accelerated tumor growth that was associated with an impaired γδ TIL response and increased CD8 TIL dysfunction. In mouse tumor models, therapeutic treatment with an agonistic anti-JAML antibody inhibited tumor growth, improved γδ TIL activation, decreased markers of CD8 TIL dysfunction, and significantly improved response to anti–PD-1 checkpoint blockade. Thus, JAML represents a novel therapeutic target to enhance both CD8 and γδ TIL immunity.

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