Benjamin Greenbaum, Member of Memorial Sloan Kettering Cancer Center, shared on LinkedIn:
“A lot of computational work in cancer immunology is devoted to predicting what antigens the adaptive immune system recognizes. These are critical questions for understanding how the adaptive immune system can kill cancer cells or how to design precision immunotherapies. Far less well quantified are what specific nucleic acids the innate immune system recognizes, and whether they are drivers of tumor initiation, evolution, and progression.
In our In Focus piece in Cancer Discovery at AACR Journals, Siyu Sun, formerly in our lab Memorial Sloan Kettering Cancer Center and now at University of Rochester Medical Center, and I propose evolutionary models for the role ‘viral mimicry‘, the sequence specific sensing of self-nucleic acids by the innate immune system, plays in cancer. The piece was inspired by our team’s paper on multisite pancreatic cancer evolution in Immunity by Cell Press with David Ting’s lab and parallel work by colleagues Charles Ishak, Daniel De Carvalho and collaborators in Cancer Discovery in ovarian cancer.
Both papers look at the role of mimicry by transposable elements, how it can drive cancer evolution, and how that is tolerized as tumors evolve.
We propose a role for specific set of viral mimics in initiation stemming from a ‘molecular echo‘ of cell intrinsic amplification of innate immunity in the germline. Such signals can alter the fitness of driver events, which then, as a trade-off, enables tolerance of a wider range of immunostimulatory nucleic acids, promoting broad chronic signaling. This picture is consistent with the work in both publications and related theoretical work.
Moreover, the specific virus-like patterns displayed, and the cognate innate receptors that can recognize them can be learned and quantified. We saw this for the first time over a decade ago, but given new computational tools there is a lot of work still to come.
As a bonus we were fortunate to have our work published with a comprehensive review of transposable elements in cancer by our TE friends Katherine Chiappinelli and Kathleen Burns. We hope you enjoy our take on this growing field!”
Title: Viral Mimicry by Repeats Mediates Evolutionary Trade-Offs in Cancer-Immune Coevolution
Authors: Siyu Sun and Benjamin Greenbaum
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