【Cell】Latest research on cancer immunotherapy: Ye Lilin/Tang Zhonghui/Professor Sun Beicheng and others have discovered new tumor memory T cells

This article is the original of the translational medicine network, please indicate the source when reprinting

Author: Jevin

Recent studies have shown that systemic tumor-responsive CD8 T cells may respond
to PD-1/PD-L1 immunotherapy.
Here, using multiple preclinical tumor models, the researchers found that tumor-specific CD8 cell subsets in tumor-drained lymph nodes (TdLNs) are not functionally depleted, but instead exhibit canonical memory traits
.
TdLN-derived tumor-specific memory cells establish memory-related epigenetic programs
early in tumorigenesis.
What's more, titanium dioxide butt adenylate anhydride interrogator cells exhibit excellent anti-tumor therapeutic effects after adoptive metastases and are characterized as true reactors of PD-1/PD-L1 blockade
.
These findings suggest that the interrupter can utilize cells to enhance anti-tumor immunotherapy
.

On October 7, 2022, the team of Ye Lilin of the All-Army Institute of Immunology of the Army Military Medical University, Tang Zhonghui team of Sun Yat-sen University School of Medicine and Sun Beicheng team of Nanjing University Drum Tower Hospital published a research paper online, using multiple preclinical tumor models, and found that tumor-specific CD8+ T cell subsets in tumor drainage lymph nodes (TdLNs) did not have functional failure, but showed typical memory characteristics
.
The study found entirely new tumor memory T cells
that can respond to immunotherapy.

of PD-1 ICB therapy

 01 

For nearly a decade, a new immunotherapy, PD-1 immune checkpoint blocking therapy (ICB), based on PD-1, has been changing the status quo
of cancer treatment.
PD-1 ICB works by blocking PD-1-mediated inhibitory signals through monoclonal antibodies, thereby reversing CD8+ T cell depletion to some extent and controlling tumor progression
.

Although the therapy has achieved good results in a series of cancer treatments, it still faces great challenges
.
First of all, some cancers with a high degree of malignancy, such as pancreatic cancer, glioma, triple-negative breast cancer, etc.
, almost do not respond to ICB, even in the type of tumor that responds, the overall response rate of patients is low, and in patients who begin to respond, most of them will have resistance in the later stages of treatment, and only a very small number of patients can benefit for a long time and achieve clinical cure
.
Nonetheless, PD-1 ICB exhibits optimal efficacy compared to targeting other immune checkpoint molecules or inhibitory signals
.
It can be predicted that PD-1 ICB will remain an important cornerstone of tumor immunotherapy at present and for some time to come, and further improving the response population and clinical cure potential of PD-1 ICB will largely depend on a deeper understanding
of the mechanism of action of PD-1 ICB.

Whether Tpex cells directly mediate the antitumor effects of PD-1 ICB

 02

CD8+ T cell depletion is a key reason why
the body's immune system cannot effectively eliminate chronic viral infections and malignant tumors.
Compared with the memory CD8+ T cells induced by acute infection or vaccine immunity, the surface of depleted CD8+ T cells continuously expresses immune checkpoint molecules including PD-1, and their proliferation potential, effect and killing function are relatively low, and they are prone to apoptosis
.
Depleted T cells were also once called "zombie" cells in the
field.

However, the discovery of depleted precursor cells (Tpex) shattered the stereotype of depleted T cells as "zombie" cells and immediately became a research hotspot
in the field of T cell depletion.
Further follow-up clinical studies have shown that this subset of cells is associated
with the efficacy of PD-1 ICB.
Based on these studies, there is a widespread view in the field that Tpex cells located within the tumor tissue microenvironment (TME) directly mediate the antitumor effects of PD-1 ICB, but there is no direct experimental evidence
for this view.
In addition, new research suggests that cells responding to PD-1 immune checkpoint therapy are derived from newly supplemented CD8+ T cell clones outside the tumor tissue, which may come from a systemic after the action of PD-1 ICB, rather than TME's local CD8+ T cell response
.

TdLN-TTSM truly responds to PD1 ICB cell subsets

 03 

Using a variety of transplant tumors and in situ tumor induction models, the researchers first detected tumor-specific CD8+ T cells in the drainage lymph nodes, and found that a certain proportion of cells expressed TCF-1 and PD-1 low, but did not express the depletion-specific transcription factor TOX
.
Importantly, this cell population (TOX-PD-1loTCF-1+) strictly complies with classical immunomemory characteristics: long-term survival independent of antigens; The antigen is encountered again, rapidly and substantially expands, and differentiates into functional effector cells; Provides long-term immune protection
.
Based on typical memory characteristics and special tissue localization, they named it tumor drainage lymph node antigen-specific memory CD8+ T cells, known as TdLN-TTSM
.

Subsequently, through high-throughput sequencing analysis, the researchers found that at the single-cell level, the transcriptional characteristics of TdLN-TTSM cells are closer to classical memory cells and more
different from depleted T cells.
In addition, after CD8+ T cells enter a depleted state, their genomes undergo some irreversible changes
at the epigenetic level of depleted molecular regions 。 By analyzing the ATAC-seq-sequencing data of TdLN-TTSM and TdLN-Tpex, they found that tumor drainage lymph nodes and Tpex cells derived from chronic viral infection, as well as Recovery Tex cells that are detached from the environment of chronic viral infection, have different degrees of chromatin opening at multiple sites of Pdcd1, Tox and other genes, but these sites are closed in TdLN-TTSM cells.
Further evidence that this particular subset of cells is not depleted T cells
.
Through a series of tumor transplantation experiments and lymphadenectomy experiments, the researchers found that after PD-1/PD-L1 ICB treatment, the antigen-specific CD8+ T cells expanded in tumor tissue were mainly derived from TdLN-TTSM, rather than the infiltrated and depleted Tex and Tpex cells
in the tumor 。 Moreover, the removal of this cell subpopulation before or during PD-1/PD-L1 ICB treatment led to the failure of PD-L1 blocking antibody-mediated immunotherapy, while the reinfusion of TdLN-TTSM cells can restore this effect, further validating that TdLN-TTSM truly responds to the PD1 ICB subpopulation
.

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This article is intended to introduce medical research advances and cannot be used as a reference for
treatment options.
For health guidance, please visit a regular hospital
.

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