Learning from Viruses How to Restore Type 1 Interferons in Cancer

Elina Isabel Zuniga, PhD
Professor, UC San Diego, Division of Biological Sciences

The Need
More than 550,000 cases of head and neck squamous cell carcinoma (HNSCC) occur annually worldwide. HNSCC is known to effectively suppress immune responses and escape immune surveillance. HNSCC-mediated suppression of adaptive immune cells has received significant attention and enabled promising immunotherapies. However, the mechanisms driving HNSCC suppression of innate cells remain poorly understood. Given that the HNSCC morbidity and mortality remain high despite advances in treatments, understanding how to properly stimulate and manipulate innate cells could illuminate new therapies and/or aid improvement of current treatments for HNSCC.

The Opportunity
Plasmacytoid dendritic cells (pDCs) are innate cells that specialize in producing outstanding amounts of type I interferons (IFN-I), which play important roles in antiviral and anti-tumor immunity. Dr. Elina Zuniga and her team have characterized a state of pDC functional suppression (or exhaustion) during chronic viral infection, where pDCs exhibit a profound compromised capacity to produce IFN-I. Remarkably, a similar pDC exhaustion state has been described in pDCs associated with different tumors, including HNSCC infiltrating pDCs. By defining the global transcriptome and chromatin landscapes in murine exhausted pDCs, Dr. Zuniga’s team has identified some candidate transcriptional regulators that could be responsible for suppressing pDC IFN-I production and causing pDC exhaustion. Relieving pDC exhaustion by manipulating these regulators may enhance immune responses against both persistent viruses and tumors.

Dr. Zuniga’s studies will define global transcriptome and chromatin landscapes in tumor-associated pDCs from HNSCC patients to identify core transcriptional regulators that exhibit conserved activity in human and murine exhausted pDCs and to assess their ability to recover pDC function when manipulated in vivo, thereby increasing antitumor immune response.

The Impact
Dr. Zuniga’s project aims at identifying novel immunotherapeutic targets in innate immune cells that can be manipulated to reinvigorate immune responses in cancer patients. This work will shed light on the mechanisms underlying a poorly studied, but highly promising, pDC exhaustion state and might illuminate new therapies to restore innate responses in patients with HNSCC as well as other types of cancer in which pDCs are functionally suppressed. Furthermore, combining approaches to reinvigorate innate responses with current treatments targeting adaptive immune cells may improve clinical outcome in cancer patients.