The promising outcomes observed in cancer immunotherapy are evidence that the immune system provides a powerful arsenal for the restriction of tumor outgrowth; however, the immunosuppressive tumor ...microenvironment (TME) is known to impair antitumor immunity and impede the efficacy of cancer immunotherapies. Regulatory T cells (Tregs), which prevent overt immune responses and autoimmunity, accumulate aberrantly in some types of tumor to suppress antitumor immunity and support the establishment of an immunosuppressive microenvironment. Ablation of Tregs has been shown to not only unleash antitumor immunity and interrupt formation of an immunosuppressive TME, but also lead to severe autoimmune disorders. Therefore, it is essential to develop approaches to specifically target intratumoral Tregs. Herein, we summarize the immunomodulatory functions of Tregs in the TME and discuss how metabolic regulation of Tregs can facilitate intratumoral Treg accumulation.
BackgroundCancer immunotherapy, including checkpoint blockade and adoptive transfer of tumor-reactive T cells, represents a paradigm shift in the treatment of malignancies in recent years, and yields ...remarkable responses by reawakening anti-tumor immunity in established tumors. Nevertheless, a significant portion of patients are refractory to cancer immunotherapies, which may be in part due to the persistent impairment of anti-tumor effector functions in T cells, a phenomenon referred to as T cell exhaustion. Emerging evidence reveal that alterations in global chromatin accessibility and de novo DNA methylation patterns are keys events to drive development of T cell exhaustion under chronic antigenic stresses. However, it remains elusive how T cells engage epigenetic reprogramming to orchestrate exhausted state.MethodsHere, we examined the mitochondrial fitness in CD8+ TILs with mitoTrackers.ResultsWe found that tumor-infiltrating tumor-reactive T cells with accumulation of damaged mitochondria, characterized by increased mitochondrial mass but reduced mitochondrial membrane potential and cristae, display more severe exhausted phenotypes, including decreased proliferation capacity, reduced cytokine production and up-regulation of co-inhibitory receptors. The accumulation of damaged mitochondria is in part due to the deficiency of mitophagy machinery. Importantly, we found that the accumulation of dysfunctional mitochondria is corelated to the specificity and affinity of antigen, and also supported by the PD-1 expression. Moreover, the combination of glucose deprivation, hypoxia and TCR signaling in vitro can drastically weaken T cell immunity with the accumulation of dysfunctional mitochondria as seen in TILs previously. Furthermore, T cells with accumulation of damaged mitochondria, generated artificially by Oligomycin A and Mdivi-1, also exhibit persistent exhaustion features. Ultimately, supplementation with nicotinamide riboside enhances T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment.ConclusionsTaken together, our study suggests that mitochondrial fitness is pivotal for T cell-mediated immunity and the accumulation of dysfunctional mitochondria could result in exhaustion phenotypes in T cells. And our findings also provide pillars for better harnessing T cell immune responses with metabolic regulations for immunotherapy.
Microbes and vitamin D aid immunotherapy Franco, Fabien; McCoy, Kathy D
Science (American Association for the Advancement of Science),
2024-Apr-26, Volume:
384, Issue:
6694
Journal Article
Peer reviewed
Vitamin D modulates intestinal epithelial cell function to enhance antitumor microbes.
Current immunotherapies yield remarkable clinical outcomes by boosting the power of host immunity in cancer cell elimination and viral clearance. However, after prolonged antigen exposure, CD8
T ...cells differentiate into a special differentiation state known as T-cell exhaustion, which poses one of the major hurdles to antiviral and antitumor immunity during chronic viral infection and tumour development. Growing evidence indicates that exhausted T cells undergo metabolic insufficiency with altered signalling cascades and epigenetic landscapes, which dampen effector immunity and cause poor responsiveness to immune-checkpoint-blockade therapies. How metabolic stress affects T-cell exhaustion remains unclear; therefore, in this Review, we summarize current knowledge of how T-cell exhaustion occurs, and discuss how metabolic insufficiency and prolonged stress responses may affect signalling cascades and epigenetic reprogramming, thus locking T cells into an exhausted state via specialized differentiation programming.
Depleting regulatory T cells (T
cells) to counteract immunosuppressive features of the tumor microenvironment (TME) is an attractive strategy for cancer treatment; however, autoimmunity due to ...systemic impairment of their suppressive function limits its therapeutic potential. Elucidating approaches that specifically disrupt intratumoral T
cells is direly needed for cancer immunotherapy. We found that CD36 was selectively upregulated in intrautumoral T
cells as a central metabolic modulator. CD36 fine-tuned mitochondrial fitness via peroxisome proliferator-activated receptor-β signaling, programming T
cells to adapt to a lactic acid-enriched TME. Genetic ablation of Cd36 in T
cells suppressed tumor growth accompanied by a decrease in intratumoral T
cells and enhancement of antitumor activity in tumor-infiltrating lymphocytes without disrupting immune homeostasis. Furthermore, CD36 targeting elicited additive antitumor responses with anti-programmed cell death protein 1 therapy. Our findings uncover the unexplored metabolic adaptation that orchestrates the survival and functions of intratumoral T
cells, and the therapeutic potential of targeting this pathway for reprogramming the TME.
The metabolic challenges present in tumors attenuate the metabolic fitness and antitumor activity of tumor-infiltrating T lymphocytes (TILs). However, it remains unclear whether persistent metabolic ...insufficiency can imprint permanent T cell dysfunction. We found that TILs accumulated depolarized mitochondria as a result of decreased mitophagy activity and displayed functional, transcriptomic and epigenetic characteristics of terminally exhausted T cells. Mechanistically, reduced mitochondrial fitness in TILs was induced by the coordination of T cell receptor stimulation, microenvironmental stressors and PD-1 signaling. Enforced accumulation of depolarized mitochondria with pharmacological inhibitors induced epigenetic reprogramming toward terminal exhaustion, indicating that mitochondrial deregulation caused T cell exhaustion. Furthermore, supplementation with nicotinamide riboside enhanced T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment. Together, our results reveal insights into how mitochondrial dynamics and quality orchestrate T cell antitumor responses and commitment to the exhaustion program.
Glycolysis, including both lactate fermentation and pyruvate oxidation, orchestrates CD8+ T cell differentiation. However, how mitochondrial pyruvate metabolism and uptake controlled by the ...mitochondrial pyruvate carrier (MPC) impact T cell function and fate remains elusive. We found that genetic deletion of MPC drives CD8+ T cell differentiation toward a memory phenotype. Metabolic flexibility induced by MPC inhibition facilitated acetyl-coenzyme-A production by glutamine and fatty acid oxidation that results in enhanced histone acetylation and chromatin accessibility on pro-memory genes. However, in the tumor microenvironment, MPC is essential for sustaining lactate oxidation to support CD8+ T cell antitumor function. We further revealed that chimeric antigen receptor (CAR) T cell manufacturing with an MPC inhibitor imprinted a memory phenotype and demonstrated that infusing MPC inhibitor-conditioned CAR T cells resulted in superior and long-lasting antitumor activity. Altogether, we uncover that mitochondrial pyruvate uptake instructs metabolic flexibility for guiding T cell differentiation and antitumor responses.
Display omitted
•Genetic and pharmacological MPC inhibition promotes memory T cell differentiation•A metabolic-epigenetic axis enables memory T cell formation upon MPC inhibition•Transient MPC blockade during CAR T cell manufacturing enhances antitumor efficacy•The MPC allows lactate oxidation to sustain antitumor function of cytotoxic T cells
Wenes et al. show that lactate oxidation via pyruvate conversion and mitochondrial import may sustain antitumor function of cytotoxic T cells in the tumor microenvironment. In contrast, short-term inhibition of the mitochondrial pyruvate carrier in recently activated T cells promotes memory differentiation, which enhances antitumor activity upon adoptive transfer therapy.
Tumor-associated macrophages (TAMs) display pro-tumorigenic phenotypes for supporting tumor progression in response to microenvironmental cues imposed by tumor and stromal cells. However, the ...underlying mechanisms by which tumor cells instruct TAM behavior remain elusive. Here, we uncover that tumor-cell-derived glucosylceramide stimulated unconventional endoplasmic reticulum (ER) stress responses by inducing reshuffling of lipid composition and saturation on the ER membrane in macrophages, which induced IRE1-mediated spliced XBP1 production and STAT3 activation. The cooperation of spliced XBP1 and STAT3 reinforced the pro-tumorigenic phenotype and expression of immunosuppressive genes. Ablation of XBP1 expression with genetic manipulation or ameliorating ER stress responses by facilitating LPCAT3-mediated incorporation of unsaturated lipids to the phosphatidylcholine hampered pro-tumorigenic phenotype and survival in TAMs. Together, we uncover the unexpected roles of tumor-cell-produced lipids that simultaneously orchestrate macrophage polarization and survival in tumors via induction of ER stress responses and reveal therapeutic targets for sustaining host antitumor immunity.
Memory CD8 T cells can provide long-term protection against tumors, which depends on their enhanced proliferative capacity, self-renewal and unique metabolic rewiring to sustain cellular fitness. ...Specifically, memory CD8 T cells engage oxidative phosphorylation and fatty acid oxidation to fulfill their metabolic demands. In contrast, tumor-infiltrating lymphocytes (TILs) display severe metabolic defects, which may underlie their functional decline. Here, we show that overexpression of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the master regulator of mitochondrial biogenesis (MB), favors CD8 T cell central memory formation rather than resident memory generation. PGC-1α-overexpressing CD8 T cells persist and mediate more robust recall responses to bacterial infection or peptide vaccination. Importantly, CD8 T cells with enhanced PGC-1α expression provide stronger antitumor immunity in a mouse melanoma model. Moreover, TILs overexpressing PGC-1α maintain higher mitochondrial activity and improved expansion when rechallenged in a tumor-free host. Altogether, our findings indicate that enforcing mitochondrial biogenesis promotes CD8 T cell memory formation, metabolic fitness, and antitumor immunity in vivo.
PDF
