Tumors frequently reactivate genes that are not otherwise expressed in normal adult tissue, including genes with prior roles in development (Fig. 1). Their expression in cancer is typically rationalized as driving cancer-relevant developmental processes such as pluripotency, proliferation and angiogenesis.

However, in recent work, we have uncovered an unexpected immunosuppressive role for such a gene: the reactivation of DUX4, an embryonic transcription factor whose misexpression also causes facioscapulohumeral muscular dystrophy (a common muscle dystrophy), suppresses antigen presentation across many cancer types, and is associated with reduced response to immune checkpoint inhibitors (Chew*, Campbell* et al. Dev Cell 2019) (Fig. 2).

In parallel, we have found several other developmental genes that are also reactivated across various cancers. Preliminary analyses have found many of these genes to be similarly associated with immune suppression in cancer, albeit in different aspects of immunity, and in different sets of cancers.

These findings suggest a generally unexplored role of many developmental genes in suppressing immunity, both in their endogenous developmental context, as well as in cancer. Understanding the mechanisms for how such reactivated developmental genes suppress the immune system will inform our approaches to the treatment of immune-evading cancers.

Our aims are to determine the molecular and gene-regulatory mechanisms underlying:

1. how reactivated developmental genes in cancer promotes immune suppression,
2. how these developmental genes become reactivated in cancer, and
3. how this immune suppression might be reversed to restore immune activity against cancers.

To do so, we take an integrative data science and experimental approach, collaborating closely with clinician scientists to iterate between mechanistically-informed analyses of patient data, and high-throughput experiments in relevant cellular and animal models.