Chinese scholars have made new progress in the field of tumor immunotherapy

Figure Tumor drainage of TdLN-T_TSM cells differentiated in lymph nodes into the tumor microenvironment to play a role

With the support of the National Natural Science Foundation of China (approval number: 32030041, 31825011), Professor Ye Lilin's team of the All-Army Institute of Immunology of the Army Medical University, together with the team of Tang Zhonghui of Sun Yat-sen University and the team of Sun Beicheng of Nanjing University, made new progress in the field of tumor immunotherapy, and for the first time found the presence of tumor antigen-specific memory CD8⁺ T cells in tumor drainage lymph nodes.
The key role
of this group of cells in the treatment of PD-1 immune checkpoint blockade (ICB) was confirmed.
The results began with "The primordial differentiation of tumor-specific memory CD8⁺ T cells as bona fide.
" responders to PD-1/PD-L1 blockade in draining lymph nodes", published online in Cell on October 7, 2022
.
Link to paper: _istranslated="1">.

CD8+ T cell depletion is the key reason why the body's immune system cannot effectively eliminate chronic viral infections and malignant tumors, and the blockade of PD-1-mediated inhibitory signals by monoclonal antibodies can reverse CD8⁺ T cell depletion to a certain extent, which is also the basis of the current clinical application of
PD-1 。 Monoclonal antibodies targeting PD-1/PD-L1 immune checkpoints have been approved for clinical treatment of a series of malignant tumors, but the therapy is almost ineffective for pancreatic cancer, triple-negative breast cancer and other tumors with a high degree of malignancy, even in effective cancers, only a small number of patients (20%-30%) can correspond, and most of the drug resistance will appear in the later stage of treatment, and only a very small number of patients can be clinically cured
.
Further improvement of the response population and clinical cure potential of PD-1 will largely depend on in-depth research on the mechanism of action of PD-1
.
In 2016, Professor Ye Lilin's group and other international research teams reported that CD8⁺ T cells (Tpex), which have a low degree of depletion in lymphoid tissue, as depleted precursor cells, functionally respond to PD-1 ICBs
.
This discovery breaks the traditional view that depleted T cells are "zombie" cells and leads the research hotspot in the field of T cell depletion, but the mechanism of air conditioning control of T cells in the microenvironment of malignant tumors in response to PD-1 ICB has not yet been clarified
.

Professor Ye Lilin's team used a variety of transplanted tumors and in situ tumor induction models to detect tumor-specific CD8+ T cells in drainage lymph nodes (TdLNs), and found that a certain proportion of cells expressed TCF-1 high and PD-1 low, but did not express the depletion-specific transcription factor TOX, which was a subset of cells (TOX-PD-1^{lo TCF-1+} Strictly consistent with classical immune memory characteristics
.
Through high-throughput sequencing analysis, they found that the transcriptional characteristics of this group of CD8⁺ T cells at the single-cell level were also closer to classical memory cells and differed greatly
from depleted T cells.
Based on typical memory features and special tissue localization, they named them tumor draining lymphnode antigen-specific memory CD8⁺ T cells, or TdLN-T_TSM (Tumor Draining Lymph Node derived Tumor Specific Memory T cell).

Further in vivo and in vitro experiments found that the removal of TdLN-T TSM cell subsets before or during PD-1/PD-L1_ICB treatment led to the failure of PD-L1-blocking antibody-mediated immunotherapy, while the return of such cells could restore this effect, further verifying that TdLN-T_TSM is a cell subset
that truly responds to PD1 ICB.

The study found novel antigen-specific memory T cells in tumor-draining lymph nodes; Break the traditional concept that "there are only depleted T cells under tumor burden, and there are no tumor-specific memory T cells"; The time-conditioning control mechanism of PD-1 ICB in tumor tissue microenvironment is improved, which provides an important theoretical basis
for further optimization of tumor immunotherapy.