Inter-metastatic divergency in small cell lung cancer; implications for the design of future immunotherapies

Abstract Aggressive malignant progression and spreading has limited a clear understanding of the pathophysiology of SCLC. The overarching goal of this “bedside to bench” project is to elucidate the role of inter-metastatic divergence in therapeutic resistance in small cell lung cancer (SCLC), with a focus on how antigenic heterogeneity and dominant immunosuppressive butyrophilins thwart protective adaptive immune responses in this disease, to develop novel interventions to overcome these hurdles. We will leverage a Rapid Tissue Donation (RTD) program established at Moofitt Cancer Center, which provides timely access to the entire repertoire of metastatic lesions in terminal patients, who generously donate their tissues for this research. Using this resource, plus CDX models routinely generated for each SCLC patient, we will define barriers that impair the effectiveness of immunotherapies. During the 5-year tenure of this grant we will generate a rationale for novel immunotherapeutic trials to overcome overcome these elusive hurdles, with a focus on antigenic heterogeneity and the role of immunosuppressive butyrophilins. Based on our expertise on tumor immunology (Dr. Conejo-Garcia) and clinical immunotherapy (Drs. Perez), as well as access to a Rapid Tissue Donation program, we postulate that the effectiveness of immunotherapies against small cell lung cancer is thwarted by heterogeneous immunogenicity across different tumor masses, along with high expression of immunosuppressive CD277+ butyrophilins. Based on our preliminary results, our central hypothesis is that pleural effusions and trogocytic tumor-infiltrating T cells could provide a source of effector lymphocytes for cell therapies that would target multiple tumor masses, in combination with targeting immunosuppressive BTN3A butyrophilins and/or tumor-derived antibodies. We propose the following Specific Aims: Aim 1. Define the role of inter-metastatic heterogeneity in therapeutic resistance in human SCLC. Aim 2. Design novel T cell immunotherapies that overcome metastatic heterogeneity in SCLC. Aim 3. Determine the potential of antibodies produced in SCLC to overcome inter-metastatic heterogeneity. These studies will, first, define the role and heterogeneity of neoantigens and immune cells in SCLC; a poorly characterized disease, due in part to its aggressiveness. Most importantly, we will provide a mechanistic rationale for more effective immunotherapies that target the diversity and dominant immunosuppressive drivers of this human disease, which will target in novel clinical trials at Moffitt.