Co-opting endogenous retroviral signaling as a lung cancer vulnerability
We recently identified a novel epigenetically regulated subclass of endogenous retroviruses (ERVs) that engages pathologic innate immune signaling in mesenchymal cancer subpopulations of Small Cell Lung Cancer (SCLC), with potentially important implications for cancer immunotherapy (Cañadas et al, Nat Med, 2018). Stimulated 3 Prime Antisense Retroviral Coding Sequences (SPARCS) are oriented inversely in 3’UTRs of certain interferon-inducible genes and silenced by EZH2. De-repression of these loci resulted in dsRNA generation following IFNs exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5’ LTR of the antisense ERV.
The overarching goal of this project is to study the biological mechanisms that connect the mesenchymal cancer resistant state to SPARCS de-repression in lung cancer, the impact on the tumor microenvironment, and co-opting this cell state to favor response to immune checkpoint blockade.
Small Cell Lung Cancer (SCLC)
Small cell lung cancer (SCLC) is an aggressive and lethal lung malignancy with a 5-year overall survival of less than 5%. While having one of the highest mutational burdens because of its strong association with tobacco smoking, SCLC is often characterized by a reduced antigen presentation and an immunosuppressive tumor microenvironment. Therefore, despite promising advances in the use of immunotherapy, only a fraction of SCLC patients respond to these therapies. SCLC is composed of phenotypically different cells with either neuroendocrine or mesenchymal features. Of note, the mesenchymal compartment enhances chemoresistance and metastatic potential of neuroendocrine cells. We and others have shown that activation of MET and/or RAS signaling can fuel this mesenchymal phenotype, resulting in chemoresistance and increased tumorigenesis in a well-established SCLC model (Cañadas et al, Clin Cancer Res, 2014). In addition, we recently showed an enhanced innate immune signaling in these SCLC mesenchymal subpopulations because of the de-repression of a novel epigenetically regulated subclass of ERVs (Cañadas et al, Nat Med, 2018).
Using SCLC as a model, we aim to identify and characterize biological mechanisms by which intratumor heterogeneity may influence the tumor microenvironment and response to therapy, providing insights in tumor immunology and informing clinical strategies to improve immunotherapies in SCLC.
Ex vivo organotypic 3D cultures to model immunotherapy response
We are developing novel functional ex vivo organotypic 3D culture platforms using surgically resected murine and patient-derived tumor samples that will allow us to validate promising therapeutic combinations in an ex vivo system that incorporates features of the tumor microenvironment and models the dynamic response to immune checkpoint blockade (Jenkins et al, Cancer Discovery, 2018).
Using this sophisticated approach, we aim to identify and characterize novel mechanisms of response and resistance to immunotherapy.