Abramson Cancer Center Support Grant

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications, trials & patents

Abstract

Cancer is the leading cause of death in people living with HIV (PLWH) in the United States and worldwide despite combination antiretroviral therapy (cART). Although the incidences of AIDS-defining malignancies have declined since the advent of cART, a number of non-AIDS?defining cancers (NADCs) appear more common in HIV-1?infected individuals relative to the general population. Hodgkin?s lymphoma (HL) represents one of the most common types of NADCs that occurs in HIV-infected individuals. The incidence of HL is 10-fold higher in PLWH relative to the general population, and the frequency of this malignancy is actually increasing in the postcART era. Several factors are associated with the rising rate in HL, but two key features are accelerated immunological aging and HIV infection, suggesting that there is interplay between HIV and immune senescence that results in an escalating occurrence of cancer development and progression. We and others have identified specific epigenetic changes associated with aberrant T cell replicative capacity that are also altered in cancer, chronic viral infection, inflammatory diseases and aging. Published work, together with our preliminary singlecell RNA sequencing studies suggest that CD8+ T cells responsible for tumor control in HL exhibit several abnormalities, including a more advanced differentiation state, poor proliferative capacity and downregulation of several genes that negatively regulate cellular senescence. The presence of a characteristic inflammatory microenvironment is a fundamental component of the tumor mass and an essential pathogenic factor in HL. In chronic HIV infection, a similar accumulation of senescent and activated CD8+ T cells and increasing levels of inflammatory factors are linked to higher risks of morbidity and mortality, indicating that specific disease processes (e.g., inflammation) likely underlie HIV-associated epigenetic changes and concomitant immunosenescence. Thus, HIV and lymphoma may have an additive influence on overlapping epigenetic pathways to accelerate aging-induced immune deterioration, resulting in loss of tumor control. However, important gaps exist in our understanding of the fundamental nature and underlying mechanisms of T cell senescence in HIV and cancer, and how those in turn, influence anti-tumor immunity; this hampers our practical ability to clinically manage these diseases and develop new effective therapies. This pilot proposal is responsive to the NIH HIV/AIDS Research High Priorities (as listed in NOT-OD15-137) through expansion of knowledge regarding the impact of pre-mature immunological aging in long-term HIV disease and the pathogenesis of NADCs. Our approach benefits from a longstanding interest in cellular immunology and determining the molecular underpinnings of age-induced immune decline in the setting of oncogenesis, tumor progression and therapeutic responses. In this vein, we recently established and operationalized a pipeline that incorporates cutting-edge transcriptional and epigenetic profiling of T cells and tissues from cancer patients and age/gender-matched healthy controls. The experiments we propose will investigate the relationship between HIV infection, cancer, immunological aging and how the health of CD8+ T cells might be related to specific epigenetic alterations. Our overall goals are to understand how chronic HIVinfection in HL contributes to the process of immunosenescence, determine the impact of epigenetic features on immune cell phenotype as well as function and identify the pathways responsible for such changes. The central hypothesis of this proposal is that CD8+ T cell immunosenecence is accelerated in HIV+ HL due to an additive pro-inflammatory environment that alters memory CD8+ T cell differentiation, homeostasis and function through epigenetic regulation of gene expression. The above hypothesis is based on findings that numerous malignancies have been attributed to epigenetic and transcriptional aberrations; these changes contribute to immune dysfunction in both chronic HIV infection and cancer. Our Specific Aims are: Aim 1. To examine the impact of HL and HIV infection on immune aging as it relates to CD8+ T cell differentiation state, telomere length, p16INK4A levels and T cell receptor (TCR) repertoire diversity in age/gender-matched cohorts of HL and HIV+ HL patients, relative to HIV- (healthy donors) and HIV+ subjects. Aim 2. To characterize the epigenetic and transcriptional landscapes of CD8+ T cells in cART-treated HIV+ HL patients using a novel pipeline that incorporates digital spatial profiling, bulk sequencing and single-cell analyses of biological samples, including cancer tissues. Both aims will explore associations between various immunosenecence signatures and levels of inflammation, immune activation and dysfunction in HIV+ HL.