Multiomics profiling reveals the benefits of gamma-delta (?d) T lymphocytes for improving the tumor microenvironment, immunotherapy efficacy and prognosis in cervical cancer

BACKGROUND: As an unconventional subpopulation of T lymphocytes, ?d T cells can recognize antigens independently of major histocompatibility complex restrictions. Recent studies have indicated that ?d T cells play contrasting roles in tumor microenvironments-promoting tumor progression in some cancers (eg, gallbladder and leukemia) while suppressing it in others (eg, lung and gastric). ?d T cells are mainly enriched in peripheral mucosal tissues. As the cervix is a mucosa-rich tissue, the role of ?d T cells in cervical cancer warrants further investigation. METHODS: We employed a multiomics strategy that integrated abundant data from single-cell and bulk transcriptome sequencing, whole exome sequencing, genotyping array, immunohistochemistry, and MRI. RESULTS: Heterogeneity was observed in the level of ?d T-cell infiltration in cervical cancer tissues, mainly associated with the tumor somatic mutational landscape. Definitely, ?d T cells play a beneficial role in the prognosis of patients with cervical cancer. First, ?d T cells exert direct cytotoxic effects in the tumor microenvironment of cervical cancer through the dynamic evolution of cellular states at both poles. Second, higher levels of ?d T-cell infiltration also shape the microenvironment of immune activation with cancer-suppressive properties. We found that these intricate features can be observed by MRI-based radiomics models to non-invasively assess ?d T-cell proportions in tumor tissues in patients. Importantly, patients with high infiltration levels of ?d T cells may be more amenable to immunotherapies including immune checkpoint inhibitors and autologous tumor-infiltrating lymphocyte therapies, than to chemoradiotherapy. CONCLUSIONS: ?d T cells play a beneficial role in antitumor immunity in cervical cancer. The abundance of ?d T cells in cervical cancerous tissue is associated with higher response rates to immunotherapy.