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Immune biomarkers in breast cancer pathology specimens : characterization and clinical implications

University of British Columbia

Immunotherapy is dramatically changing the landscape of cancer treatment and is becoming incorporated into the standard of care for some tumor types. Until recently, breast cancer has not been generally considered particularly immunogenic. However, breast cancer is a heterogeneous disease and increasing evidence suggests that patients with basal-like breast cancer, an aggressive subtype lacking targeted therapy options, may be amenable to immunotherapy. My research goals have included the investigation and clinical characterization of two emerging targetable immune checkpoint biomarkers: lymphocyte-activation gene 3 (LAG-3) and the T-cell Immunoglobulin and Mucin domain-containing molecule 3 (TIM-3), by applying immunohistochemistry to a well-annotated tissue microarray cohort of 3,992 breast cancers. As an additional research goal, I evaluated a novel in situ multiplex biomarker assessment method (Nanostring-based digital spatial profiling-DSP) for its compatibility with breast cancer tissue microarrays, to generate immune profiles from patient surgical specimens. I report that the expression of LAG-3 or TIM-3 on intra-epithelial tumor-infiltrating lymphocytes (iTILs) was observed in a minority of cases (11%) in the whole cohort, but was significantly enriched in basal-like breast cancers (33% and 28% of basal-like breast cancers being infiltrated with LAG-3+ and TIM-3+iTILs, respectively). Furthermore, I found that LAG-3+iTILs and TIM-3+iTILs were present in breast cancers co-infiltrated with established immunotherapy targets (program cell death-1/PD-1 and its ligand, PD-L1). In multivariate analyses, LAG-3+iTILs or TIM-3+iTILs were independent favorable prognostic factors in breast cancer patients. In the last part of the thesis, I profiled the tumor immune microenvironment of two basal-like-enriched breast cancer cohorts, quantifying the expression of 31 immuno-oncology biomarkers using DSP. I then validated the digital counts for CD8 and PD1 by comparing with immunohistochemistry, and CD45 digital counts by comparing with hematoxylin & eosin-stained stromal TILs counts. Lastly, I identified a 4-biomarker signature indicative of a pre-existing immunity in breast cancer patients. The body of work presented here may help guide the selection of breast cancer patients for clinical trial evaluation of emerging immunotherapy agents. Furthermore, I show that digital spatial profiling technology can efficiently and quantitatively profile immune expression on breast cancer patient specimens using only a tiny fraction from precious tumor samples.

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2019-06-12

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/70622

Pathology and Laboratory Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/