Nature Cancer Zhang Zemin's research group and collaborators reveal 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 in the international journal Nature Cancer A research paper entitled Temporal single-cell tracing reveals clonal revival and expansion of precursor exhausted T cells during anti-PD-1 therapy in lung cancer , proposed the concept of clonal revival and revealed PD-1 antibody therapy The mechanism of action in lung cancer
.

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

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 [1]
.

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

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

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 that existed 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

In addition, the Howard Chang research group of Stanford University proposed the concept of clonal replacement, which believed that the clonal types of tumor-specific T cells in tumors after treatment were newly emerged [7]
.

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)

　　Figure 2 Clonal revival

　　Baolin Liu, a doctoral student from the BIOPIC/School of Life Sciences at Peking University, Dr.
Hu Xueda from BIOZ, and Dr.
Feng Kaichao from 301 Hospital are the co-first authors of the paper
.

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

　　Link to the paper: https://　　references:

　　[1] Simoni et al.

　　[2] Caushi et al.

　　[3] Oliveira et al.

　　[4] Ahmadzadeh et al.

　　[5] van der Leun et al.
, CD8 + T cell states in human cancer: insights from single-cell analysis, Nat Rev Cancer (2020).

　　[6] Pauken et al.
, Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade, Science (2016).

　　[7] Yost et al.
, Clonal replacement of tumor-specific T cells following PD-1 blockade, Nat.
Med.
(2019).