The objective of this proposal is to define the role of a p53-dependent non-canonical DNA damage response and how its reactivation of transposable elements (TE) can be leveraged to stimulate effective immunotherapy in cancer. The premise we will investigate is that combining epigenetic modulation with stimulation of the p53-DUX4 axis will allow for TE reactivation and potent sensitization of cancer cells to immunotherapy.

Although checkpoint-based immune-therapy has yielded impressive clinical results, most patients do not respond likely because they exhibit poor basal tumor immunity. A deeper understanding of how to leverage...

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The objective of this proposal is to define the role of a p53-dependent non-canonical DNA damage response and how its reactivation of transposable elements (TE) can be leveraged to stimulate effective immunotherapy in cancer. The premise we will investigate is that combining epigenetic modulation with stimulation of the p53-DUX4 axis will allow for TE reactivation and potent sensitization of cancer cells to immunotherapy.

Although checkpoint-based immune-therapy has yielded impressive clinical results, most patients do not respond likely because they exhibit poor basal tumor immunity. A deeper understanding of how to leverage TE activation turning “cold cancers” into “hot cancers” may make this therapy more effective, especially in pediatric cancers like rhabdomyosarcoma, which often exhibit a low mutation rate and are thus difficult to treat with immunotherapy.

We will:

1. Aim1: Identify epigenetic synergies between the non-canonical DNA damage response (DDR) activation of DUX4 and repetitive element network in rhabdomyosarcoma. Determine which epigenetic factor(s) mediate de-repression of DUX4 and identify which epigenetic factors allow for synergistic TE activation.
2. Aim 2: Investigate molecular mechanism(s) by which the DUX4 target gene Zscan4 blocks cell death during chemotherapy. Identify which protein domains within Zscan4 are necessary to inhibit cell death after p53 activation. Determine how Zscan4 prevents p53 binding or p53 target gene activation thus facilitating cell survival.
3. Aim3: Characterize the ability of DUX4-actived dsRNA to stimulate anti-tumor immunity. Determine which class of DUX4-targeted TE most potently reactivates dsRNA innate immune sensing. Using a cancer organoid/immune cell co-culture system, identify which class of DUX4 activated TE recruits/activates autologous T cells to promote anti-tumor immunity.

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