Nature Cancer Zhang's research group revealed the characteristics of tumor-specific T cells and the mechanism of immunotherapy at the multi-cancer level

On September 23, 2022, the research group of Zhang Zemin of Peking University's Biomedical Frontier Innovation Center (BIOPIC), School of Life Sciences, and Beijing Future Gene Diagnostics Advanced Innovation Center (ICG) published a report entitled "Single-cell meta-analyses reveal responses of tumor-reactive CXCL13+ T cells to" in the international journal Nature Cancer Research paper
on immune-checkpoint blockade.

Identifying the characteristics of tumor antigen-specific CD8 T cells in the tumor microenvironment and their differentiation status is key
to understanding the mechanism of tumor immunotherapy.

By analyzing a public single-cell dataset containing CD8 T cell gene expression and corresponding antigen-specific information, combined with published datasets of tumor-infiltrated CD8 T cells with pre- and post-treatment pairings, the study found that the expression of CXCL13 can accurately identify both terminally differentiated and depleted tumor-specific T cell clones and tumor-specific T cell clones with low levels of depletion in response to tumors after ICB treatment (Figure 1).

Figure 1 CXCL13 identifies tumor-specific CD8 T cells in different differentiating states in tumors before and after ICB treatment

To explore the mechanism of ICB action on tumor-specific CD8 T cells on multiple cancer species, the researchers collected nine published immunotherapy single-cell datasets, including 205 tumor samples from 102 patients before and after treatment, covering 5 cancer types (NSCLC, BCC, SCC, breast cancer & RCC
).

Figure 2 Tumor-specific CXCL13+ CD8+ T cell changes before and after ICB treatment

Previous studies of basal cell carcinoma (BCC) and breast cancer [5,6] have found a significant increase
in tumor-specific T cells with terminal differentiation and high levels of depletion after effective ICB treatment.

To further explore this phenomenon, the researchers performed clustering analysis of tumor-specific CXCL13+CD8+ T cells, identified precursor tumor-specific CXCL13+CD8+ T cells (including IL7R+HAVCR2- and GZMK+HAVCR2- two subtypes) and end-differentiating tumor-specific T cells with strong depletion signals, and found tumor-specific CXCL13+CD8+ T cell subtypes of different differentiated states are epistemically stable (Figure 3
).

Figure 3 Relationship between CXCL13+ CD8+ T cell subtype and ICB therapy

In CD4 T cells, ICB significantly increased CXCL13+ CD4+ T cells (Figure 4), indicating that this taxon is the dominant class of CD4 T cells that respond to ICBs, consistent with recent studies finding that CXCL13+ CD4+ T cells are able to recognize and process tumor antigens specifically [11].

Figure 4 CXCL13+ CD4+ T cells with immunotherapy

The scientific findings of the study (1) provide new ideas for analyzing tumor-specific T cells in tumors; (2) Provides accurate biomarkers for predicting the efficacy of ICB; (3) Provides a new strategy for the design of cell therapy represented by TCR-T, that is, to identify tumor-specific T cell clones at different differentiation stages in tumors by CXCL13 expression levels and design follow-up clinical trials; (4) It provides new insights to further improve the efficacy of ICB, that is, to further alleviate the immunosuppressive intensity in the tumor microenvironment through the combination of ICB and other therapies, maintain the precursor tumor-specific CXCL13+ CD8+ T cell state and block its differentiation to the terminal state, and then continue to improve the therapeutic effect
.

Baolin Liu, a doctoral student at Peking University's BIOPIC/School of Life Sciences, was the first author of the paper, and Dr.

Paper Link:_msthash="320092" _msttexthash="4247867"> Corresponding to Commentary article:_msthash="320093" _msttexthash="168129"> References:

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