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This project explores the nature of the immune infiltrate in human breast cancer (BC) with the goal of identifying critical compositional and organizational differences related to clinical outcomes. Our previous work found that organized tertiary lymphoid structures (TLS; see Figure), forming in the peri-tumoral stroma of BC, are characterized by the specific presence of CD4+ follicular helper T (Tfh) cells and CXCL13 expression, both predictive for positive outcomes (Gu-Trantien et al. 2013 J. Clin. Invest). Our recent prospective study of fresh BC tissues shows that the extent of tumor infiltrating lymphocytes (TIL) within our cohort forms a continuum (see Figure; Buisseret et al., in revision for Oncoimmunol.), a curve that is maintained irrespective of patient numbers (current cohort n>725 patients). We further find that important compositional differences, which are not linked to the extent of tumor infiltration alone, are clinically relevant (Gu-Trantien et al., manuscript in preparation).

Our current work involves both prospective studies to understand the functionality of specific TIL subpopulations and how they organize into TLS as well as retrospective studies that seek to apply these findings to a grading system that scores an individual patient’s anti-tumor immune response for use in BC treatment decisions (immunological grade). The Molecular Immunology laboratory is investigating the following specific questions:

• What is the prognostic and predictive value of detecting TIL and TLS in BC?
• Are their compositional differences in TIL and TLS that are associated with differences in clinical outcome?
• What are the molecular mediators that regulate CD4+ T and B cell infiltration in BC?
• What are the roles that specific specific subsets of CD4+ T and B cell TILs play in anti-tumor immune responses and clinical outcome?
• How does aberrant expression of the transcription factor FOXP1 play a role in CD4+ T cell persistence and expansion and is this linked with anti-tumor immunity?
• Are their links between anti-tumor immune responses and specific mutations in triple negative BC? In HER2+ BC?
• What are the clinically relevant immune checkpoint molecules expressed in BC?
• Can we implement an immunological grade for BC that helps to guide treatment decisions for conventional chemotherapy, radiotherapy and/or new immunotherapies?

Ultimately, our goal is to further understand how we the power and the specificity of the immune response can be harnessed to produce effective and sustained anti-tumor immunity.