The interplay of social and molecular determinants in lung cancer disparity

点击翻译按钮获取中文摘要

Abstract African Americans (AAs) are disproportionally affected by lung cancer, compared with all other racial and ethnic groups in terms of incidence and survival. Disproportionate diagnosis of aggressive disease and poor survival among AAs highlights the critical need for further studies that characterize racial differences in lung cancer. Our goal is to address this vital knowledge gap by identifying molecular, biological, and social characteristics (neighborhood-level factors) underlying the disease’s aggressiveness, thereby reducing the disparity between African Americans (AAs) and European Americans (EAs). Our central hypothesis is that CC chemokine receptor-6 (CCR6) and its only natural ligand CCL20 add to the racial difference in molecular footprint and immune landscape, impacting racial disparity in lung cancer aggressiveness and prognosis. In addition to these biological factors, social factors associated with chronic stress, which elevated cortisol, shape the immunological landscape differently in AAs, contributing to racial differences in aggressiveness and prognosis. There is a unique possibility that CCR6/CCL20 and social characteristics contribute to the disparity in lung cancer among AAs, which has never been explored. Hence the proposed work will enhance understanding of cell biological traits of aggressive lung cancers, particularly non-small cell lung cancer (NSCLC), which accounts for ~85% of the lung cancers that underlie ethnic disparities in disease outcomes and mechanisms by which cells acquire aggressive phenotypes. To accomplish these goals, we have assembled a multidisciplinary research team with complementary expertise in cancer immuno-biology, oncology, pulmonary care, pathology, public health/behavioral science, bioinformatics, and biostatistics to investigate the following aims: A1. Establish the association of CCR6-CCL20 axis in NSCLC aggressiveness and therapeutic response among AAs and EAs; A2. Ascertain the race-specific differences in the immunological landscape contributing to the NSCLC disparity and A 3. Determine the impact of social stress on the immune signature among AA and EA NSCLC patients. Completion of these aims will i) inform a rapid, non-invasive chemokine based detection methods which will allow classifying potentially fatal lung cancers, ii) a method for early patient stratification so that risk-adapted chemokine-based therapies can be designed to match patient subgroups with distinct CCR6 profiles, iii) to offer more effective treatment approach, iv) a framework for improving the success rate of clinical trials involving investigational drugs by establishing new criteria for patient classification, Immune-based strategies to reduce disparity and, v) identify geospatial neighborhood characteristics impacting the immune system and outcome in lung cancer aggressiveness and therapeutic outcome on which evidence-based intervention can be developed to address the disparity in lung cancer.