Date of Award

January 2020

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Lajos Pusztai

Abstract

African American (AA) women with triple-negative breast cancer (TNBC) are less likely to respond to neoadjuvant chemotherapy and have poorer prognosis than White American (WA) patients with TNBC, suggesting potential tumor biological differences by race. We test the hypothesis that the immune microenvironment differs between self-defined AA and self-defined WA patients. RNA-seq expression data were obtained from The Cancer Genome Atlas (TCGA) database for 162 AA and 697 WA breast cancers (TNBC: n=58 AA, n=114 WA). Immune-related gene expression, tumor infiltrating lymphocyte (TIL) counts, as well as somatic DNA aberration loads, were compared by race and tumor subtype. TNBC formalin-fixed paraffin embedded (FFPE) tissue and corresponding clinical data were also collected for 54 AA and 56 WA TNBC cases from Yale Cancer Center (YCC). RNA was extracted and sequenced, and tumor sections underwent quantitative immunofluorescence (QIF) staining in multiplex. Immune-related gene expression, TIL counts, and localization of immune cell population markers were compared by race. Among TCGA cases, immune metagene analysis demonstrated marginal immune attenuation in AA TNBC relative to WA TNBC that did not reach statistical significance. Among YCC cases, immune metagene analysis revealed a trend towards increased interferon signaling, T cell infiltration and T cell inhibition pathways in AA relative to WA TNBC that did not reach statistical significance, and QIF suggested higher CD8+ T cell and macrophage infiltration as well as PD-L1 expression in AA TNBC. These results suggest that immunological differences between AA and WA patients with TNBC exist, and AA patients may benefit from PD-L1 blockade therapy due to robust infiltration of T cell populations.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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