In parallel with proteins, microRNA (miRNA) represents an entirely new domain of functional molecules encoded by the human genome. Besides their bona fide functions to regulate RNA transcriptions inside the cell, mature miRNA are found in the tumor environment and the peripheral blood, and interact with the innate immune system as extracellular signaling molecules. These cancer-associated miRNA are potentially immunogenic considering they are differentially expressed between cancer and healthy tissues, stable, and have molecular weights around 7 kDa. In our preliminary studies, cancer-associated miRNA were screened for activating human dendritic cells (DC) based on morphological changes, maturation status and secretion of pro-inflammatory cytokine/chemokine(s). Activation of human DC was found to coincide with immunological responses against a couple of cancer-associated miRNA detected preferentially in patients with prostate and lung cancer but not non-malignant donors. As a result, a sensitive and robust method for quantifying autoantibody (Ab) responses against miRNA has been developed in our laboratory with the potential to become novel biomarkers for a number of cancers. The hypothesis for this study is that some cancer-associated miRNA may function as danger signals and induce IgG Ab responses as a result of cancer manifestation. IgG Ab responses against cancer-associated miRNA are thus attractive cancer-specific biomarkers. To test the above hypothesis in light of the preliminary data, we propose to screen cancer-associated miRNA and validate the specificity of IgG Ab responses against cancer-associated miRNA determinants (aim 1). We will retrospectively assess Ab responses against cancer-associated miRNA alone or as part of the A+PSA platform assay for early detection of prostate cancer. This will be conducted in collaboration with San Antonio Center of Biomarkers of Risk for Prostate Cancer using a large cohort of prostate cancer patients as well as age- and racial/ethnic background-matched healthy males (aim 2). Due to the limited sensitivity and specificity for miR-17 and -21-sepcific autoAb alone, this study is not intended to develop ready-to-use biomarkers; it rather opens doors for new biomarkers centered on miRNA-specific autoAb. Furthermore, owning to the highly important roles miRNA play in regulating oncogenesis, cell cycle, apoptosis, inflammation, and other hallmarks of human cancers, immune responses against cancer-associated miRNA have great promise as tools to aid early detection, diagnosis, and prognosis of multiple human cancers.
Recent success of immune checkpoint inhibitors demonstrated the power of tipping the balance of naturally occurring immune responses against cancer, of which autoantibodies (Ab) against tumor-associated antigens are an important arm. In this exploratory study, we seek to establish the methodology to measure miRNA-specific autoAb and to build up a panel of miRNA recognized by autoAb for early prostate cancer detection. Successful detection of early stage and indolent prostate cancer may reduce the overall cost of prostate cancer management.
