Mapping the epitope of anti-IsoAspELAVL4 immune responses in SCLC patients and an SCLC mouse model 3763

Abstract Description Small cell lung cancer is the most aggressive type of lung cancer, with a 5-year survival of 8%; new therapies are urgently needed. Pulmonary neuroendocrine cells, the progenitors of SCLC, express the RNA-binding protein ELAVL4. ∼15% of SCLC patients naturally develop an anti-ELAVL4 antibody response (previously called “anti-Hu”) and show an improved response to therapy and significantly improved survival. We determined that the antigenic epitope of ELAVL4 is linked to isoaspartylation (a type of protein damage) of the unstructured ELAVL4 N-terminal region (aa 1-38) resulting in a tumor-specific neo-antigen: isoAsp-ELAVL4. We recently showed that we can actively induce an immune response against an N-terminal Elavl4 polypeptide incubated under isoaspartyl-inducing conditions, and that this leads to a significantly increased survival in a mouse SCLC model. However, the specific site(s) of isoaspartylation within the N-terminal region remain to be determined. Isoaspartylation occurs at asparagines and aspartates, 8 of which are present in the ELAVL4 N-terminal region. Four ELAVL4 N-terminal deletion mutants were designed for recombinant protein production. These will be used to epitope map using SCLC patient and mice sera with an existing anti-ELAVL4 response through western blotting and ELISA assays. Mapping the specific isoAsp-ELAVL4 response will be crucial for the future generation of monoclonal antibodies as new targeted SCLC therapies. Funding Sources Supported by the Robert E. and May R. Wright Foundation Transformative Cancer Research Grant, USC’s Undergraduate Research Associated Program, Judy Glick, and Conya Pembroke. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)