Cancer Center Support Grant

University Of California Los Angeles, Los Angeles CA

Investigators

Linked publications, trials & patents

Abstract

HIV infection is associated with a greatly increased risk for the development of non-Hodgkin lymphoma (NHL). Nearly all AIDS-related lymphomas (ARL) are of B cell origin. Two major mechanisms are believed to contribute to the genesis of ARL: 1) loss of immunoregulation of EBV+ B cells resulting from impaired T cell function, and 2) chronic B cell activation leading to DNA-modifying events that contribute to oncogene mutations/translocations. HIV infection has long been known to be associated with chronic, polyclonal B cell activation and, more recently, has been associated with microbial translocation. Recently, it has been shown that HIV, inflammatory cytokines and LPS can induce a B-regulatory cell (Breg) phenotype. Bregs are CD24+CD38+ B cells with regulatory functions that secrete IL10. Moreover, we have observed that Bregs are elevated prior to ARL development and that these cells express Program cell Death Ligand (PDL1). Additionally, we have preliminary data showing that NHL and ARL cell lines secrete PDL1+ exosomes, which have been shown to have prognostic value in cancer: PDL1+ exosomes are elevated in the circulation of patients that are non-responders to immunotherapy. More importantly, we have observed that PDL1+ exosomes are detectable in plasma from ARL patients and that plasma levels of these exosomes decrease following treatment. Therefore, we propose that PDL1+ exosomes may be a good biomarker for ARL risk and/or prognosis, and that PDL1+ exosomes are induced by inflammatory cytokines and LPS, which are known to be elevated prior to the development of ARL and also are known to induce PDL1 expression, as well as the secretion of exosomes. In this study we propose studies to determine if: 1) inflammatory cytokines and/or LPS can induce the secretion of exosomes containing PDL1 or B7 receptors, 2) exosomes containing PDL1 and B7 receptors have the capability to regulate T cell function, including anti-tumor effector functions, and 3) in vivo levels of circulating PDL1+, PDL2+, CD80+, CD86+and CD40L+ exosomes are associated with levels of serum markers of microbial translocation and/or inflammatory cytokines, and if circulating exosomes are good biomarkers for ARL risk and prognosis. This project serves as a supplement to P30CA016042. UCLA Jonsson Comprehensive Cancer Center?s goal is to advance studies that aim to define cancer risk to inform prevention, treatment, and foster survivorship; decode initiation and evolution of cancer; understand individual cancers at unprecedented levels to improve patient treatment and outcomes; and harness the body?s immune system to control and treat cancer.