The Role and Clonal Diversity of Tumor-infiltrating Lymphocytes in Breast Cancer

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

DESCRIPTION (provided by applicant): Basal-like breast cancer is a subtype of breast cancer associated with high rates of relapse and poor outcomes, and has relatively few treatment options. Basal-like breast cancer is also often associated with large numbers of tumor-infiltrating lymphocytes (TILs). Luminal A breast tumors make up a subtype associated with much better survival outcomes, and typically lack TILs. The presence of TILs has been shown to predict improved survival outcomes among basal-like breast tumors, but not among Luminal A breast tumors. These data suggest the presence of subtype-specific tumor antigens amenable to immune targeting. However, the TIL populations responsible for this immune response have not been well characterized. Aim 1 will clarify the association of different TIL cell types with breast cancer subtype, prognosis, and other clinical features in breast cancer. Gene expression signatures of distinct TIL cell types will be identified from existing literature and hierarchical clustering of gene expression microarray data, and these signatures will be used to stratify clinically annotated breast cancer gene expression data sets. Aim 2 will determine the cellular phenotypes, physical architecture, and prevalence of TILs in Basal-like and Luminal A breast cancers. Human tumors and mouse models of Basal-like and Luminal A breast cancers will undergo immunohistochemical and flow cytometric analyses of immune cell markers. Aim 3 will establish the clonal diversity of TILs and peripheral blood lymphocytes in mouse models of Basal-like and Luminal A breast cancer. T-cell and B-cell lymphocyte clones can be uniquely identified by the rearranged T-cell or B-cell receptor they express. The diversity of these receptors expressed in a lymphocyte population can differentiate an antigen-driven response characterized by expansion of one clone (reduced receptor diversity) and a nonspecific immune response (high receptor diversity). T-cell and B-cell receptor genes will be isolated from tumor and peripheral blood RNA and amplified by PCR, then high-throughput sequencing will be used to clarify the level of clonal restriction of the lymphocyte populations. The proposed aims will characterize the lymphocytes potentially targeting a subset of Basal-like breast tumors. These lymphocytes hold promise as a tumor marker or potential therapeutic target for immunogenic Basal-like breast tumors.