01
Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity
Yajing Qiu. et al.
Cancer Cell. 2024
This study explores the potential of restoring mannose metabolism to enhance T cell function, offering a novel approach for cancer immunotherapy. The authors identify metabolic dysfunction, including impaired glucose, amino acid, and fatty acid metabolism, as a key factor in T cell dysfunction, limiting the efficacy of adoptive T cell therapies. They demonstrate that D-mannose supplementation reprograms T cell metabolism, epigenetics, and O-GlcNAcylation, promoting the generation of stem-like T cells. This enhances T cell stemness and self-renewal, paving the way for “off-the-shelf” CAR T or TCR T cell products. D-mannose metabolism produces M-6-P, which inhibits glycolysis by targeting enzymes like hexokinase and phosphate-glucose isomerase, redirecting metabolic flux into the TCA cycle and activating compensatory glutamine-driven reductive carboxylation. This metabolic shift increases α-KG levels, modulating histone demethylase activity and altering epigenetic modifications (e.g., H3K4me3 and H3K27me3) to support T cell stemness. Additionally, D-mannose enhances O-GlcNAcylation by upregulating OGT expression, stabilizing β-catenin, and boosting the expression of stemness-related transcription factors Tcf7 and Lef1. In vivo experiments reveal that oral D-mannose not only suppresses tumor growth but also enhances radiotherapy and immunotherapy by inducing tumor cell death and promoting PD-L1 degradation. Furthermore, D-mannose mitigates chemotherapy-induced intestinal damage and immune checkpoint blockade (ICB)-related colitis without compromising antitumor efficacy. Given that nearly half of ICB-treated patients experience colitis as a side effect, D-mannose’s dual role in enhancing T cell function and reducing toxicity suggests its potential to improve both the efficacy and safety of cancer immunotherapies.
DOI: 10.1016/j.ccell.2024.11.003
02
Nouran S Abdelfattah. et al.
Immunity. 2024
This study introduces T-Switch, a novel engineering platform designed to systematically evolve T cell receptors (TCRs) for targeting specific antigens, particularly self-antigens, while avoiding cross-reactivity and maintaining specificity. The platform employs a two-step strategy: first, TCRs are evolved to recognize a neo-epitope peptide with a single amino acid change, bypassing central tolerance. Next, the complementarity-determining region 3 (CDR3) of the TCR is systematically mutagenized to create a diverse library, allowing for specificity to switch from the neo-epitope to the desired target. Proof-of-concept experiments with NLV TCRs demonstrated the feasibility of this approach. By introducing 2-3 amino acid changes in the CDR3 region, the platform successfully switched TCR specificity between closely related epitopes. Importantly, this strategy focused on **swapping specificity**—losing the original epitope recognition while acquiring recognition of a new epitope—minimizing off-target effects and cross-reactivity compared to affinity-matured TCRs.
Applying T-Switch to the neuroblastoma self-antigen TH, engineered TCRs achieved the following:
1. Specific targeting and killing of tumor cells presenting the TH antigen.
2. Lack of cross-reactivity with other peptides in a proteome-wide T-Scan screen.
3. Potent in vitro tumor cell killing.
4. Effective anti-tumor activity in in vivo adoptive transfer models.
This study highlights the plasticity of the TCR-pMHC interface, which enables precise specificity tuning. The platform’s ability to circumvent self-tolerance and adapt to any desired target presents broad therapeutic potential, such as detecting rare cell types or delivering agents to specific cells. Overall, T-Switch represents a promising tool for generating cancer-reactive TCRs for adoptive cell therapy (ACT) and future biomedical applications.
DOI: 10.1016/j.immuni.2024.11.009
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