Project Summary/Abstract Extracellular vesicles (EVs) have gained considerable attention as mediators of intercellular signaling and as potential sources of cancer biomarkers. Exosomes, which are nanoscale EVs of endocytic origin, are present in nearly all types of biofluids, carrying a tremendous potential for liquid biopsy and therapeutic applications. Exosomes deliver cargo containing immunoregulatory molecules such as receptors, ligands, antigens, and/or cytokines. This cargo can be reflective of the cell of origin and have effects on recipient cells. Salivary exosomes have been identified as highly informative nanovesicles with clinically relevant information. Salivary exosomes have brought forth a pathway and mechanism in which tumor-derived biomarkers can be shuttled through the systemic circulating into the oral cavity. Despite such clinical potential, the role of salivary exosomes for the host and tumor has been greatly understudied. We hypothesize that salivary exosomes have immunomodulatory effects through mucosal immune system. In this project, we will determine the unique peptide repertoire loading salivary exosomes in the setting of tumor. Identifying the salivary peptides that can activate or inhibit lymphocytes will provide new insights into the immune control of tumor and may uncover novel targets and strategies for immunotherapeutics. Moreover, identifying novel tumor- or host-derived antigens released into saliva will provide not only insight into its potential regulatory function but also the diagnostic value.