​Experts comment on Nat Immunol | Overcoming T cell depletion-Metabolic reprogramming releases great potential for tumor immunotherapy to treat solid tumors

Comment | Chief Editor Chi Hongbo | Xi A story of T cell exhaustion and reinvigoration © LBI / EPFL / Kathlia Hu Tumor immunotherapy is a new type of treatment method to treat tumors by activating or rebuilding the patient's immune system.

At present, tumor immunotherapy such as immune checkpoint blockade (ICB) or adoptive immune cell transfer (ACT) technology has achieved remarkable clinical therapeutic effects in some tumor patients.

However, the current outstanding problem is that most cancer patients do not respond to tumor immunotherapy.

In particular, chimeric antigen receptor T cells (CAR-T) are currently only used for the treatment of hematomas, and their therapeutic effects on solid tumors are very limited.

One of the main reasons is that tumor infiltrating lymphocytes (TILs) are continuously stimulated by tumor antigens in the tumor microenvironment, which causes T cell exhaustion.

Recently, it was discovered that according to the expression of T cell surface molecules (PD-1, TIM-3) and the transcription factor TCF-1, the depleted T cells in the tumor microenvironment can be divided into two main subgroups.
The precursor depleted T cells Cells (PD-1+TCF-1+TIM-3–, progenitor exhausted T cell) and terminally exhausted T cells (PD-1+TCF-1–TIM-3+, terminally exhausted T cell).Among them, precursor-depleted T cells have almost no tumor-killing activity and can be transformed into terminal-depleted T cells; terminal-depleted T cells still retain part of the tumor-killing ability and directly control tumor growth.

However, the proliferation ability of terminally depleted T cells is impaired.
Without effective intervention, terminally depleted T cells will further lose their proliferation ability and cytotoxicity, become non-functional T cells, and gradually lose the ability to control tumor growth.
(See the diagram below).

However, terminal depletion of T cells does not respond to most current immunotherapy methods such as PD-1 antibodies.

Therefore, T cell depletion, especially the inactivation state of terminal depleted T cells that is difficult to prevent or reverse, has become a major bottleneck restricting the entire field of tumor immunotherapy.

© LBI / EPFL / Yugang Guo May 24, 2021, led by Professor Tang Li from the Federal Institute of Technology in Lausanne, in conjunction with Ludwig Cancer Research Center, University of Lausanne, West China Medical College of Sichuan University, New York University Abu Dhabi, and University of Science and Technology of China, etc.
The research team of scientific research institutes published an article "Metabolic Reprogramming of Terminally Exhausted CD8+ T cells by IL-10 Enhances Anti-Tumor Immunity" in Nature Immunology, and developed a new tumor immunotherapy based on metabolic reprogramming for Preventing or reversing T cell exhaustion provides new ideas for curing solid tumors.

In this study, the researchers synthesized a fusion protein of interleukin-10 and IgG1 Fc fragment (IL-10–Fc) and found that IL-10–Fc can significantly inhibit the growth of solid tumors.

In a variety of mouse solid tumor models, IL-10–Fc combined with ACT or ICB can completely eliminate solid tumors.

The study further confirmed that IL-10–Fc promotes the proliferation of terminally depleted T cells and their anti-tumor immune response by enhancing mitochondrial pyruvate carrier (MPC)-dependent oxidative phosphorylation (OXPHOS), which has significantly expanded The scope of application of T cell-dependent tumor immunotherapy.

Initially, the authors found that IL-10–Fc can significantly increase the proportion and number of PD-1+TIM-3+CD8+ T cells in mouse B16F10 tumor tissue.

Further studies have found that the phenotype of PD-1+TIM-3+CD8+ T is basically the same as the terminally depleted T cells of PD-1+TCF-1–TIM-3+, which suggests that IL-10–Fc may promote Expansion of eventually depleted T cells.

The increase in the number of terminal-depleted T cells may be due to the transformation of precursor-depleted T cells, the expansion of terminal-depleted T cells themselves, or the down-regulation of terminal-depleted T cell apoptosis.

Through a series of in vivo and in vitro experiments, especially through Tcf7DTR-GFP transgenic mice (this mouse model can achieve specific removal of precursor-depleted T cells through drug treatment), the authors found that IL-10–Fc has an effect on terminal depletion of T cells.
The number expansion does not depend on the existence of precursor-depleted T cells, and it is finally confirmed that IL-10–Fc can directly act on the depleted T cells to promote their proliferation and tumor-killing activity.

Next, the authors confirmed that the effect of IL-10–Fc depends on the metabolic reprogramming of terminally depleted T cells.

Through the analysis of metabolic pathways, the authors found that the pyruvate-MPC-OXPHOS metabolic pathway is essential for IL-10–Fc to enhance the proliferation and metabolism of T cells.

With the help of MPC knockout mice, the authors further confirmed that MPC is an indispensable key molecule for IL-10–Fc to promote the metabolism, proliferation and anti-tumor immune response of terminally depleted T cells, and then revealed a way to prevent or reverse T cell depletion , A new metabolic regulation pathway that enhances the efficacy of tumor immunotherapy.

© EPFL / Alain Herzog Dr.
Guo Yugang and PhD student Xie Yuqing from the research group of Professor Tang Li are the co-first authors of this paper.

Dr.
Guo Yugang put forward the initial idea of ​​this research, Xie Yuqing assisted in designing the experiment, and the two and their collaborators completed all the experiments.

Professor Tang Li and Professor Ping-Chih Ho of the Ludwig Cancer Research Center of the University of Lausanne are the co-corresponding authors of the paper.

Original link: https://doi.
org/10.
1038/s41590-021-00940-2 Expert comment Chi Hongbo (St.
Jude Children's Research Hospital, St.
Jude Children's Research Hospital) Although current tumor immunotherapy can control tumors to a certain extent Growth rate, but the effect is very limited in curing tumors.

This study shows that IL-10/Fc can directly act on terminally depleted T cells, enhance the OXPHOS metabolism of terminally depleted T cells, significantly improve their proliferation ability and tumor killing activity, and then achieve the cure of solid tumors (in the joint ACT or ICB conditions).

The study found that the metabolic reprogramming of OXPHOS related to the pyruvate-MPC metabolic pathway is sufficient to reactivate the terminally depleted T cells, which brings new knowledge for the exploration of how cell metabolism determines the fate of T cells, and also for the development of the next generation of tumor immunotherapy Drugs have brought new targets.

This study also shows that although terminally depleted T cells do not respond to conventional immunotherapeutic drugs such as PD-1 antibodies, they can still respond to metabolic regulation drugs, which points out a new direction for the development of better tumor treatment drugs in the future.

The research also has potential clinical translational value.

Experiments have proved that the injection of IL-10-Fc in the mouse model will not cause direct toxicity problems such as weight loss and liver function damage to the host, showing good safety.

More importantly, IL-10-Fc can significantly improve the efficacy of tumor immunotherapy and increase the response rate to immunotherapy.
Its potential clinical transformation value includes at least the following two points: 1.
Improve chimeric antigen receptor T cells (Chimeric The curative effect of antigen receptor T cell (CAR-T) or tumor infiltrating lymphocytes (TILs) adoptive immunotherapy: CAR-T is currently clinically mainly used in the treatment of hematoma, and its therapeutic effect on solid tumors is very limited.

TILs adoptive immunotherapy has achieved a certain effect in patients with melanoma, but it still cannot cure tumors or achieve long-term survival of tumor patients.

According to the therapeutic effect of IL-10-Fc combined with ACT in this project, it will provide guarantee for the successful application of CAR-T or TILs adoptive immunotherapy in the treatment of solid tumors, and even realize the cure of tumors or the long-term survival of tumor patients.

It is worth mentioning that in the above-mentioned IL-10–Fc combined with ACT treatment model, lymphodepletion pretreatment is not used (IL-10–Fc can also activate the host’s endogenous exhausted T cells ).

This will significantly reduce the clinical toxic and side effects caused by lymphatic clearance, and will also greatly increase the clinical application of IL-10-Fc and ACT combination therapy.

2.
Improve the response rate and efficacy of immune checkpoint antibodies: At present, immune checkpoint antibodies represented by PD-1 antibody have been clinically used in many solid tumors, but the overall response rate is only about 20%.

This project found that IL-10-Fc can significantly improve the therapeutic effect of PD-1 antibody on insensitive tumors (CT26).

Unlike the PD-1 antibody and other ICB therapies, IL-10–Fc can directly activate terminal-depleted T cells, thereby complementing the function of PD-1 antibody, significantly improving insensitive tumors (especially the lack of precursor-depleted T cells in tumor tissues).
Tumor) response rate to PD-1 antibody. Therefore, it is worth looking forward to, clinically, IL-10-Fc may also significantly improve the response rate and efficacy of immune checkpoint antibodies, bringing a leap in immune checkpoint antibody therapy technology.

In conclusion, tumor immunotherapy based on metabolic regulation may become a new milestone after immune checkpoint antibodies, laying the foundation for curing tumor patients in the future.

Tang lab introduction and recruitment informationEngineering immunity-disease interactions for enhanced cancer immunotherapyTang lab's research aims at developing novel strategies to engineer immunity-disease interactions, an emerging field called'immunoengineering', through chemical, metabolic, and mechanical means in order to treat cancer safely and effectively with immunotherapies.
We are actively looking to recruit PhD students and postdoctoral researchers who are interested in this new field and would like to work in a highly interdisciplinary environment.
For more information, please see our publications below or website (tang-lab .
epfl.
ch) and reach out to li.
tang@epfl.
ch.
Highly motivated and talented candidates with excellent academic achievements in a major field of Immunology, Cancer Biology, Bioengineering, or a closely related discipline, are encouraged to apply.
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