Findings have identified key T cell subsets for immunotherapy response

The team of Professor Xu Ruihua of Sun Yat-sen University Cancer Prevention and Control Center, together with Zhang Haiyan, associate researcher of the Faculty of Health Sciences, University of Macau, revealed the immunological basis of the treatment sensitivity of EBV (Epstein-Barr virus)-positive gastric cancer patients, and discovered the key T cell subsets of immunotherapy response, which is expected to provide a new therapeutic direction for EBV-positive gastric cancer patients. The relevant results were recently published in Signal Transduction and Targeted Therapy.

Schematic diagram of the research mechanism. Photo courtesy of the research team

Through dynamic single-cell transcriptome sequencing and paired immunopanel libraries, the researchers performed a fine analysis of the tumor immune microenvironment of EBV-positive and negative gastric cancer before and after immunization combined with chemotherapy. By systematically comparing the tumor microenvironment immune characteristics of EBV-positive and negative gastric cancer patients, they found that the EBV-positive gastric cancer microenvironment is immuno-inflammatory with abundant T cell and B cell infiltration, reflecting the complex interaction between EBV infection, immune cell ecosystem and tumor.

Further analysis revealed that in EBV-positive gastric cancer patients, there was an EBV antigen-specific subset of CD8+ T cells (ISG-15+CD8+ T cells), which were precursored T cells and exhibited stem cell properties: including strong proliferative ability and potential to differentiate into depleted T cells. By dynamically and accurately comparing the association between the composition and proportion changes of different immune cells and treatment effects, the researchers found that higher baseline levels of ISG-15+CD8+ T cells were able to predict better immunotherapy responses.

The researchers also found that CD8+ T cells with high expression of CXCL13 in the tumor microenvironment showed significant clonal expansion after effective treatment, showing strong tumor killing ability. CD8+ T cells that do not respond to tumor infiltration in patients express the inhibitory immune checkpoint-LAG3 and gradually enter a state of terminal depletion. Therefore, it is speculated that LAG-3 may be a potential new target for immunotherapy in EBV-positive patients.

Based on this finding, the research team recommended two patients with refractory EBV-positive gastric cancer to participate in the clinical trial of LAG3 inhibitors, and found that LAG3 antibodies effectively inhibited tumor growth and reduced peripheral blood EBV-DNA copy number. Targeting LAG3 may be a new therapeutic direction for EBV-positive gastric cancer patients. Xu Ruihua, co-corresponding author of the paper and professor of the Cancer Center of Sun Yat-sen University, said. (Source: China Science News, Zhu Hanbin, Zheng Minshan)

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