Research Project
10399834
Project Summary/Abstract Platinum chemotherapeutics are the primary treatment for nonsmall cell lung cancer (NSCLC), but due to the prevalence of resistance to these compounds, the addition of PD-1 immunotherapy has become the standard of care. However, chemotherapy has been shown to impact anti-tumor immunity by inducing PD-1 expression, CD8+ T cell priming, and infiltration leading to immunogenic cell death. There is an urgent need to understand the molecular mechanisms by which platinum-based chemotherapeutics impact the immune response in NSCLC. To analyze the paradoxical effects of platinum compounds on the immune system, a systemically designed and novel bank of platinum compounds with structural similarities to FDA-approved chemotherapeutic will be used. Aim 1) In cellular models of lung cancer, the cell surface expression patterns of T Cell activators will be examined. Both matrix metalloproteases and class I major histocompatibility complex, which play a role in metal sensitivity, will be analyzed before and after exposure to the platinum compounds. We hypothesize that leaving ligand differences of platinum compounds will impact the levels of these factors on the cell surface, correlating to the cell-type-specific variances in platinum toxicity. Aim 2) The impact of the novel platinum compounds on the adenosine dependent pathway through the production of tumor-derived prostaglandin E2 (PGE2) and modulation of the cell surface expression of CD73 will be determined. Our hypothesis is that production of adenosine is stimulated by the indirect effects of chemotherapy on M-MDSCs via the following steps: (a) chemotherapy induces PGE2 production in tumor cells; (b) the released PGE2 upregulates CD73 ecto- 5?-nucleotidase enzyme on the surface of M-MDSCs; (c) CD73 catalyzes the production of adenosine from AMP (derived from ATP released by dying cells); and (d) adenosine inhibits the activation of effector CD8+ T cells within the tumors. The long-term goal of this proposal is to understand the mechanisms that mediate platinum resistance and toxicity in NSCLC, ultimately leading to strategies to block any immunosuppressive effects of chemotherapy. The study is innovative in both the signaling model proposed for the blockade of the immune system and in the design of the platinum compounds that vary only at the leaving ligand.
