Dr Philip on the Development of T-Cell Dysfunction in Liver Cancer and Melanoma Cell Models

Mary Philip, MD, PhD, associated director, Vanderbilt Institute for Infection, Immunology and Inflammation; assistant professor, medicine, Division of Hematology/Oncology, Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, discusses research investigating the key transcriptional and epigenetic programs that regulate CD8 T-cell fate decisions in the context of cancer, and how these can potentially be leveraged to enhance antitumor immunity.

Philip and colleagues aimed to address the issue of T-cell dysfunction in tumors by investigating the earliest stages of T-cell infiltration into tumors. Previous research has identified certain transcription factors, such as TOX, which upregulate inhibitory receptors and other programs in dysfunctional T cells, Philip begins. However, knocking out TOX alone was not found to significantly improve T-cell function, Philip reports. This finding prompted a deeper investigation into the initial moments after T cells enter tumors, with the hypothesis that understanding these early stages could provide insights into reprogramming dysfunctional T cells, Philip explains.

Contrary to the belief that T-cell dysfunction develops over days or weeks, the study focused on the first few hours after T cells infiltrate tumors, using models of late-stage liver cancer and metastatic melanoma, Philip details. The researchers found that T cells began exhibiting dysfunction within hours of encountering antigens. This rapid onset of dysfunction was unexpected and indicated that the critical changes occur much earlier than previously thought, Philip notes.

Although the study aimed to identify a few key transcription factors differentiating functional from dysfunctional T cells at these early time points, the findings revealed a complex landscape with numerous transcription factors already dysregulated in the initial hours, Philip continues. However, one notable pattern was the lack of activation in certain inflammatory-driven transcription factors, such as members of the IRF and STAT families, in dysfunctional T cells, Philip adds.

To address this, Philip is exploring strategies to rescue early T-cell dysfunction by introducing external inflammation, which is not typically present in the tumor environment. For example, Philip and colleagues are investigating the use of Listeria monocytogenes to induce inflammation, potentially restoring T-cell function by enhancing the inflammatory signals that are deficient in the tumor milieu.