Understanding the role of genomic “dark matter” in the immune response to tumors

MedicalResearch.com Interview with:
Benjamin Greenbaum, PhD
Assistant Professor and
Professor Nina Bhardwaj MD PhD
Hematology and Medical Oncology
Tisch Cancer Institute
Icahn School of Medicine at Mount Sinai
New York, NY 10029

Medical Research: What is the background for this study?

Response: It has recently become clear that, due to epigenetic alterations, tumors transcribe non-coding RNAs that are typically silenced. Often such RNA emanates from the “dark matter” genome. Many of these regions consist of repetitive elements and endogenous retroelements that are rarely transcribed in normal tissue. At the same time, due to immunotherapy, understanding the role of the immune system and immune activation in tumors has become critically important. The activation of specific elements of the innate immune system in a tumor may have either beneficial or detrimental effects for patients. Moreover, recent work has suggested that endogenous element activation can lead to improved immunotherapy outcomes. Therefore, it is critically important to understand the nature of innate immune activation in tumors and what triggers are responsible for these responses.

We have been developing methods to detect abnormal patterns in viral RNA that may indicate activation of the innate immune system. We have found that patterns of motif usage avoided in the evolution of viruses, such as influenza, indicate RNA features that provoke an innate immune response. The innate immune system is capable of sensing motifs in viruses. We tested directly whether these avoided patterns are immunostimulatory.

Medical Research: What are the main findings?

Response: We used a novel quantitative approach, derived from methods in statistical physics, to characterize all of the non-coding RNA transcribed by normal tissue and compared them to the non-coding RNA found in tumors. We found that while the non-coding RNA transcribed in normal tissue displays patterns of motif usage consisting with that of coding RNA, the RNA transcribed in tumors, yet rarely found in normal tissue, can have motif usage more typically associated with viral and bacterial genomes. We predicted a handful of such RNA are immunostimulatory and validated this prediction in antigen presenting cells. We then showed that this sensing may come from a subset of the innate immune system associated with pathogen RNA sensing. We called these RNA “i-ncRNA”, for immunostimulatory non-coding RNA.

Medical Research: What recommendations do you have for future research as a result of this study?

Response: The biggest challenges are to identify the components of the innate immune response in tumors for which these RNA are responsible. Better characterization of more i-ncRNA, and their association with specific pathways, would help us better understand their role in the tumor microenvironment. We could then better their link them to patient outcomes and when they could be utilized for patient therapy.

Citation:

Antoine Tanne, Luciana R. Muniz, Anna Puzio-Kuter, Katerina I. Leonova, Andrei V. Gudkov,David T. Ting, Rémi Monasson, Simona Cocco, Arnold J. Levine, Nina Bhardwaj,and Benjamin D. Greenbaum

Distinguishing the immunostimulatory properties of noncoding RNAs expressed in cancer cellsPNAS 2015 112 (49) 15154-15159; published ahead of print November 2, 2015,doi:10.1073/pnas.1517584112

Benjamin Greenbaum, PhD, & Professor Nina Bhardwaj MD PhD (2015). Understanding the role of genomic “dark matter” in the immune response to tumors