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The mechanism of anti-PD-1 immunotherapy in lung cancer
The mechanism of anti-PD-1 immunotherapy in lung cancer.
On December 23, 2021, Peking University Biomedical Frontier Innovation Center (BIOPIC) , School of Life Sciences, Beijing Future Gene Diagnosis Advanced Innovation Center (ICG) Zhang Zemin’s research group and 301 Hospital Han Weidong’s research group published a question on Nature Cancer It is of precursor exhausted T cells during anti- PD-1 therapy in lung cancer Temporal single-cell tracing reveals clonal revival and expansion of research papers, proposed cloning revival (clonal revival) concept and reveals PD-1 antibody treatment in lung cancer Mechanism of action in.
Immunotherapy represented by anti-PD-1 has significantly improved the pattern of cancer treatment, but immunotherapy only works in a part of cancer patients.
In order to promote the development of next-generation immunotherapy, it is first necessary to understand the mechanism of action of anti-PD-1 therapy.
The researchers collected tumor samples from lung cancer patients before and after anti-PD-1 treatment, used single-cell sequencing to systematically track the dynamic changes of T cells before and after treatment, and analyzed the difference between responding patients and non-responsive patients ( Figure 1) .
Figure 1 Project research plan and main findings
Tumor infiltrating T cells include not only tumor-specific T cells that can recognize tumor antigens and kill cancer cells, but also T cells that specifically recognize non-tumor antigens such as influenza viruses, and non-tumor-specific T cells account for a large portion of tumors Proportion  .
Therefore, how to exclude the potential impact of non-tumor-specific T cells and accurately study the dynamic changes of tumor-specific T cells is a challenge in the analysis process.
Multiple previous studies have shown that due to the continuous stimulation of tumor antigens, tumor-specific CD8 T cell clones in tumors will simultaneously highly express T cell killing and “depletion” related genes, while non-tumor-specific CD8 T cells will not express “Exhaustion” of related genes [2-4] .
Therefore, in tumors, depleted CD8 T cells can be used as a substitute for tumor-specific T cells  .
The researchers developed a new set of analysis ideas (Figure 1) . First, cluster analysis was used to identify the depleted CD8 T cell group, and then based on the TCR sequence of the depleted CD8 T cell clone, all CD8 T cells were divided into tumors Specific CD8 T cells and non-tumor-specific CD8 T cells: According to the conclusions and hypotheses mentioned above, cells with exactly the same TCR sequence as depleted CD8 T cells are tumor-specific T cells, and the rest are non-tumor-specific T cells.
The study found that among responding tumors, treatment significantly increased the proportion of tumor-specific T cell precursor cells with low depletion signals, indicating that PD-1 antibody may block the differentiation of tumor-specific T cells to a depleted state.
On the contrary, this trend was not observed in tumors that did not respond before and after treatment.
There are three possibilities for the increase of tumor-specific T cell precursor cells after effective treatment:
1. Reversal of depleted T cells;
2. Expansion of precursor cells previously present in the tumor;
3. T cells from outside the tumor such as peripheral blood Supplement.
The researcher eliminated the first possibility through correlation analysis and emphasized the importance of the latter two modes.
The reversal of depleted T cells is a long-standing hypothesis in the field, but previous mouse studies have shown that the apparent modification and characteristics of depleted T cells are stable and difficult to change  .
The researchers’ analysis of human tumors further supports this view.
In addition, the Howard Chang research group of Stanford University previously proposed the concept of clonal replacement , which believed that the clonal types of tumor-specific T cells in tumors after treatment were newly emerged  .
The study found that in the process of lung cancer treatment, both new clones and previously existing clones will be recruited into the tumor to perform functions (Figure 2) .
In response to this phenomenon, researchers put forward the concept of clonal revival , which expanded the model of clonal replacement.
The scientific findings of the study revealed the mechanism of anti-PD-1 therapy in lung cancer, and provided new ideas for the development of new clinical detection and treatment methods.
Figure 2 Clonal revival
North BIOPIC / School of Life Sciences doctoral student Liu Baolin , Baiao Newell Hu Xue Da Dr. and 301 hospitals Feng Kai super doctoral thesis tied for the first author.
Professor Zhang Zemin of Peking University BIOPIC/School of Life Sciences and Professor Han Weidong of 301 Hospital are the co-corresponding authors of the paper.
 Simoni et al., Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates, Nature (2018).
 Caushi et al., Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers, Nature (2021).
 Oliveira et al., Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma, Nature (2021).
 Ahmadzadeh et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood (2009).
 van der Leun et al., CD8 + T cell states in human cancer: insights from single-cell analysis, Nat Rev Cancer (2020).
 Pauken et al., Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade, Science (2016).
 Yost et al., Clonal replacement of tumor-specific T cells following PD-1 blockade, Nat. Med. (2019).
the mechanism of anti-PD-1 immunotherapy in lung cancer
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