Cell: Army Military Medical University found the presence of tumor antigen-specific memory CD8+ T cells in tumor draining lymph nodes

On October 7, 2022, the international top journal "Cell" published online the important research results completed by the team of Ye Lilin/Xu Lifan and collaborators of the Department of Immunology, School of Basic Medical University of Army Medical University, "The.
primordial.
differentiation.
of tumor-specific memoryCD8+T cells as bona fide responders to PD-1/PD-L1" blockade in draining lymph nodes”
。 The study is the first to identify the presence of tumor antigen-specific memory CD8+ T cells in tumor-draining lymph nodes and confirms the critical role
of this group of cells in PD-1 immune checkpoint therapy for cancer.
This is a continuation of the work of the research group published in Nature in 2016, Professor Ye Lilin of the University is the first corresponding author of the paper, and it is also the first time that the scientific research results completed by the university have been published in "Cell", and the relevant research results have once again received widespread attention
from the academic community.

Professor Ye Lilin introduced that the tumor suppressive microenvironment induces the depletion
of tumor-specific CD8 T cells that infiltrate.
Depleted CD8 T cells persistently high express a series of inhibitory immune checkpoint receptor molecules, including PD-1
.
PD-1 blocking antibody has been widely used in the clinical treatment of a series of malignant tumors, but its target cells and mode of action have not yet been clarified
.
It is generally believed in the field that PD-1 blocking antibodies mainly act on depleted CD8 T cells infiltrated in tumors, reverse their depletion, and thereby enhance their anti-tumor effector function
.
However, the team's published data (He, Nature, 2016) and other recent studies do not support this view
.

Using a variety of transplanted tumors and in situ tumor induction models, the research team first tested tumor-specific CD8+ T cells in draining lymph nodes, and found that a certain proportion of cells expressed TCF-1 high and PD-1 low, but did not express depletion-specific transcription factor TOX
.
Importantly, this cell population (TOX-PD-1loTCF-1+) strictly conforms to the classical immune memory characteristics: 1.
long-term survival independent of antigens; 2.
encounters antigens again, rapidly expands substantially, and differentiates into functional effector cells; 3.
provides long-term immune protection
。 Based on typical memory features and special tissue localization, they named them tumor draining lymphnode antigen-specific memory CD8+ T cells, or TdLN-TTSM (Tumor Draining Lymph Node derived Tumor Specific Memory T cells).

This cell population is closer to classical memory cells at the transcriptional level and differs greatly
from depleted T cells.
In addition, TdLN-TTSM is also detached from the gene fixation modification site (epigenetic scar)
characteristic of depleted CD8+ T cells at the epigenetic level.

Functionally, TdLN-TTSM cells showed significantly better tumor inhibition ability
than Tpex and Tex.
Moreover, through a series of tumor transplantation experiments and lymph node resection experiments, it was found that after PD-1/PD-L1 ICB treatment, the antigen-specific CD8+ T cells expanded in tumor tissues were mainly derived from TdLN-TTSM, rather than the infiltrated and depleted Tex and Tpex cells
in the tumor 。 Removal of this cell subset leads to the failure of PD-L1-blocking antibody-mediated immunotherapy, both before or during PD-1/PD-L1 ICB therapy; The return transfusion of TdLN-TTSM cells can restore this effect, further verifying that TdLN-TTSM is a cell subset
that truly responds to PD1 ICB.

Professor Ye Lilin, the first corresponding author of the paper, is the secretary general of the Immune Cell Branch of the Chinese Society of Cell Biology, a recipient of the National Science Foundation for Outstanding Young Scholars, a leading talent of the 10,000 people program, and the chief scientist
of 973.
Associate researcher Xu Lifan won the National Science Foundation for Outstanding Young Scholars, the Chongqing Outstanding Youth Science Fund, and the Future Female Scientist Award
of the China Association for Science and Technology.
The research team has long focused on basic and translational research on T cell responses to viral infections and malignant tumors, and has achieved a series of original results, which have been published in Nature (2016), Cell (2022), Nature Immunology (2015, 2021), Nature Medicine (2018), Immunity (2017) and Cell Host & Microbe (2022).

。

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