Although immune checkpoint blockade targeting the PD-1/PD-L1 axis has seen enormous success in some cancer patients, many are unresponsive to this treatment, limiting its effectiveness. However, the ways in which tumors evade PD-1/PD-L1 immunotherapy remain incompletely understood. Recently, Brendon Stiles and his team discovered that the enzyme ADP-ribosyltransferase 1 (ART1) may play an important role in one mechanism of resistance in lung cancers. ART1 mono-ADP-ribosylates the P2X7 receptor (P2X7R) on immune cells, which ultimately causes cell death in T cells, macrophages, and dendritic cells. They found ART1 to be highly expressed in multiple human non-small cell lung cancer cell lines and in the majority of human lung adenocarcinomas they sampled, allowing these cancers to blunt the immune response against them. Indeed, they found that inhibiting ART1 with a monoclonal antibody in mouse models of lung cancer caused a dramatic reduction of tumor burden, and enrichment of immune cells in the tumor.
In this project, the Stiles group will continue their work investigating ART1 as a tractable target for lung cancer and explore its therapeutic potential in other cancers such as melanoma, breast, colon, and glioblastoma. They will examine the cellular localization of ART1 in cancers cells in mouse models upon different treatment conditions, such as radiation therapy and immunotherapy. P2X7R expression levels will be measured on immune cells before and after treatment with an anti-ART1 antibody, and the tumor cell response under different conditions will be measured. Finally, they will examine the ART1-P2X7R axis in human tumors which are both treatment naïve and those which have been treated. Ultimately, they hope to identify a broad panel of tumors that strongly express ART1. By understanding how ART1 is regulated and affects the local tumor immune microenvironment, they will identify the appropriate context in which to begin clinical trials targeting this pathway.
Wennerberg E, Mukherjee S, Sainz RM, Stiles BM. The ART of tumor immune escape. Oncoimmunology. 2022.