Role of the stromal microenvironment in B-cell lymphoma progression and immune escape

项目总结/文摘

PROJECT SUMMARY/ABSTRACT This project focus in the biology of diffuse large B-cell lymphoma (DLBCL) that are common aggressive malignancies with a curability rate of 65% despite intensive chemoimmunotherapy. DLBCL represents a significant clinical problem for disparities research in that it is a potentially curable cancer, but one that is universally fatal if untreated or improperly treated. Untreated DLBCL patients have an expected survival of <1 year, whereas with modern standard chemoimmunotherapy >58% of patients are alive and cured at 5 years. The collective work of investigators involved in this administrative supplement demonstrated that despite the high cure rates for DLBCL, outcomes remain heterogeneous. In fact, for DLBCL patients who are of African ancestry outcomes are significantly worse: in the US, African American (AA) patients were diagnosed on average 10 years younger, more commonly presented with advance stage disease, and had worse overall survival than their white counterparts. These disparities in lymphoid malignancies sparked interest in elucidating the role of genetic ancestry in influencing differences among populations. As proposed in the parent R01, using transcriptomic analysis of the lymphoma microenvironment for 4,655 DLBCLs, we defined four major lymphoma microenvironment (LME) categories that associate with distinct biological aberrations and clinical behavior independently to previously described genomic DLBCL subgroups. All these studies, genomic and transcriptomics, have been focused primarily on populations of European descent, with no or minimal representation of AA patients. However, there remains a gap in knowledge regarding the relationships between the LME and clinical and demographic factors associated with worse survival including AA ancestry, rural status, insurance status, and socio-economic status. In this supplement, we will close this gap by exploring these relationships in an AA cohort study characterizing LME subtypes in relation to genomic alterations in cancer cells. Thus, we propose the following Specific Aims: Specific Aim 1: Elucidate the characteristics of the LME in AA DLBCL patients and the relationship with the epigenome; and Specific Aim 2: Characterize CAF and ECM phenotypes in genetically defined LME DLBCL categories across multiethnic cohort. Our proposal will address for the first time the role of the microenvironment in the biology and clinical outcomes in AA DLBCL patients. We will determine the influence of race and ancestry in tumor biology and tumor immune responses associated with African ancestry and their potential therapeutic and prognostic implications.