Immunotherapeutic approaches—those that use the body’s own immune system to help fight cancer—have revolutionized the treatment of melanoma. However, only some patients respond to these treatments. In others, tumors are able to shield themselves from T cells, the body’s main weapon against cancer cells, by producing high levels of the intracellular messenger beta-catenin. In their paper “Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity,” Stefani Spranger, PhD, and Thomas Gajewski, MD, PhD, of the Department of Pathology and Riyue Bao, PhD, of the Center for Research Informatics describe the pathway by which these tumors prevent invasion by T cells, and also suggest ways to circumvent this mechanism and improve treatment in resistant tumor types.
The research team identified beta-catenin as the likely relevant factor by analyzing and comparing tumor tissue samples from 106 patients whose tumor tissue exhibited T cell–driven inflammation and 91 whose tumors were resistant to T cells, using genomic data from The Cancer Genome Atlas. CRI bioinformatician Riyue Bao used our Bioinformatics Core resources to perform the analysis of this exome-sequencing data, which included assessing the expression of six beta-catenin target genes. The analysis revealed that far more of the tumors that blocked T cells had a high level of beta-catenin signaling than those that did not block T cells.
The researchers then used experiments in mice to confirm this finding and unravel the details of how the beta-catenin signaling pathway works to block T cells and prevent inflammation. They also experimented with potential interventions that could disrupt this pathway and found that injection of a specific type of dendritic cell into tumors overcame T cell resistance and allowed inflammation to occur. This discovery could lead to improving the effectiveness of immunotherapeutic treatment in patients with these resistant tumors—and although the study pertained to melanoma, the researchers believe the findings are likely to be applicable across many types of tumors.