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

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

Correspondingly, these co-inhibitory receptors, along with T-cell depletion-related genes such as CD39, can accurately identify tumor antigen-specific T cells
in treatment-naive tumors.

(1) Tumor-specific T cells with terminal differentiation and high degree of depletion

(2) Tumor-specific T cell precursor cells with low degree of depletion remain a problem
.

On September 22, 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 titled "Single-cell meta-analyses reveal responses of tumor-reactive CXCL13+ T cells to" at Nature Cancer Research paper
on immune-checkpoint blockade.

Through the analysis of public data sets, this study proposes a method of identifying tumor antigen-specific T cells in the tumor microenvironment before and after CXCL13 expression level (ICB) treatment, identifies the different differentiation states and characteristics of tumor-specific CD8 T cells, and reveals the mechanism
of immune checkpoint blockade (ICB) at the cellular level from the multi-cancer level.

By analyzing a public single-cell dataset containing CD8 T cell gene expression and corresponding antigen-specific information, combined with published tumor-infiltrating CD8 T cell datasets 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 tumors-specific T cell clones with low levels of depletion in response to ICB therapy (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's 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 have found a significant increase
in tumor-specific T cells with terminal differentiation and high levels of depletion after effective treatment of ICB.

In addition, studies have shown that ICB further increases the killing capacity of terminal differentiated tumor-specific CD8 T cells, so that significantly increased (1) tumor-specific T cells with strong end-differentiated and depletion signals after effective treatment of ICB are observed in different cancer types can effectively kill cancer cells and cause tumor reduction
.

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 depletion-signaling terminally differentiated tumor-specific T cells, and found tumor-specific CXCL13+CD8+ T Cell subtypes of different differentiation states are epitactically stable (Figure 3
).

The researchers found that treatment of subclasses of tumor-specific T cells that cause increased growth was different in different cancer types and when treatment strategies varied (e.

Figure 3: CXCL13+ CD8+ T cell subtype in relation to ICB therapy

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

In addition, the study found that simultaneously measuring the proportion of CXCL13+CD4+ T and CXCL13+CD8+ T cell classes in tumors could more accurately predict the efficacy of ICBs, with prediction accuracy > 90% in multiple cancer types (Figure 4) and significantly higher performance than the traditional marker TMB
.

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 combination therapy with ICB and other therapies, maintain the precursor tumor-specific CXCL13+ CD8+ T cell state and block its differentiation to the terminal state, thereby continuing 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.

Original Source:

Liu， B.