DESCRIPTION (provided by applicant): Classical Hodgkin lymphoma (cHL) is the most common form of lymphoma affecting people under the age of 30 in the Western World. Treatment responses after initial therapies are excellent in young people, however late effects cause considerable mortality and morbidity. 25- 30% of patients experience relapse or progressive disease following initial treatment and 5-15% die of their disease within 10 years. An improved understanding of the pathobiology of cHL is an essential requirement for biomarker development and novel therapeutic approaches to improve initial and late outcomes. cHL is unique among cancers in that the malignant cells comprise less than 1% of the tumor with the remainder of the tumor microenvironment (TME) composed of a variety of immune cells. We have shown that in some populations, the composition of the TME affects cHL outcome. Here we will examine the correlation between the TME composition and survival in cHL across, age, sex, EBV status, histology and racial/ethnic groups (Aim 1). We will also examine the effect of host factors (age, sex, race/ethnicity, SES), EBV status and histology on TME composition (Aim 2) and we will conduct analyses to determine whether TME mediates or interacts with host factors to impact survival (Aim 3). This will be the largest study of cHL TME conducted to date and the only one designed to specifically examine relationships in different racial/ethnic and age groups. To conduct this study, we have assembled a multidisciplinary team of experts. We will perform gene expression profiling (our validated Scott Predictor) using NanoString and we will examine specific T-cell and other subsets, including macrophages and B-cells, implicated in outcome, using immunohistochemistry on formalin-fixed paraffin-embedded diagnostic biopsies from 2,688 U.S. multiethnic cHL patients from 5 large clinical centers. EBV DNA in the tumor cells will also be measured. Tissue microarrays will be constructed and immunohistochemistry automatically scored. We will also collect demographic and clinical data including age, race/ethnicity, sex, socioeconomic status, treatment, progression-free and overall survival, B symptoms, anatomic site, stage and other information. With this sample size, the minimum detectable Hazard Ratio (HR) with 80% power is 1.55 to 1.32 for a TME binary variable with frequency ranging from 0.1 to 0.5, respectively. The ranges of detectable marginal HR are well-within the range of previously observed effects and should enable us to test marginal effects by race/ethnicity, age and other factors. The significance of this proposal lies in identifying population differences for a cutting-edge clinical biomarker and elucidating the immunobiology of the TME in different demographic groups.

PUBLIC HEALTH RELEVANCE: Classical Hodgkin lymphoma (cHL) is the most common form of malignant lymphoma affecting people under the age of 30 in the Western World. Treatment responses after initial therapies HL are excellent, especially in adolescents and young adults. However late effects due to aggressive treatment cause considerable illness and even death, including second cancers, heart, and lung disease. In addition, between 10-20% of patients die of their disease within 5 years (depending on stage at diagnosis). Thus, tests that can predict which patients need aggressive treatment would be highly beneficial. Classical Hodgkin lymphoma tumors are unusual because the tumor cells themselves make up only about 1% of the tumor. The majority of the tumor consists of various immune cells, such as different types of lymphocytes which reflect the patient's response to the tumor. We have found that certain cells in the background of the tumors (called tumor microenvironment) can predict relapse and survival but the studies have been limited largely to young adult whites. Knowledge gaps on how the tumor microenvironment can predict outcome in non-whites and patients across age groups is completely lacking. In addition, there are suggestions but little is know about the effec of patient characteristics such as age, sex or race/ethnicity on the tumor microenvironment. In this proposal, we plan to study the cells in the tumor microenvironment of 2,688 classical Hodgkin lymphoma patients of different ages and racial/ethnic groups, including 654 Hispanics, 539 African-Americans and 195 Asians. This has never been attempted and our group of scientific experts has the best chance to examine how host respose (tumor microenvironment) varies and impacts survival across populations.