It is now well established that chronic infiltration of leukocytes into neoplastic tissue potentiates solid tumor development. Many experimental and clinical studies have revealed that tumor-promoting leukocytes regulate essentially all aspects of cancer development. However, the molecular natures of individual leukocyte subtypes associated with developing breast cancers (BCs) are inadequately understood. Our overarching hypothesis is that leukocyte biomarkers in human BC can provide prognostic and predictive information regarding BC outcomes, and that these can also be utilized as platforms for design of new, individualized diagnostic and therapeutic agents. This TMEN proposal is based on our collective goal of generating a comprehensive understanding of the composition and transcriptome characteristics of leukocytes in normal breast tissue as compared to BC. Based on identification of predictive immune-based biomarkers that correlate with BC stage, outcome or response to therapy, we will generate innovative, clinically applicable diagnostic and possibly therapeutic, or combined "theragnostic" "probes" for non-invasive in vivo molecular image analysis. Development of these novel and unique reagents will advance our understanding of the tumor microenvironment in BC. As such, we predict that the immune microenvironment In BC can be utilized and exploited to not only predict risk of recurrent disease, and response to therapy, but also to monitor response to therapy and together, these advances will improve outcomes for patients with BC. As such Project 1 will Identify clinically significant leukocyte biomarkers in breast cancer. Project 2 will reveal correlation of outcomes in human breast cancer with leukocyte transcriptomes and novel leukocyte biomarkers;and Project 3 will drive translation of leukocyte biomarkers into clinically applicable diagnostic and therapeutic probes

Public Health Relevance

Development of leukocyte-selective imaging reagents will facilitate Identification of a patient population likely to benefit from novel immune-based therapeutic strategies, as well as enabling monitoring patients during therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA163123-03
Application #
8337729
Study Section
Special Emphasis Panel (ZCA1-SRLB-3 (O1))
Program Officer
Mohla, Suresh
Project Start
2011-09-23
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$365,455
Indirect Cost
$63,865
Name
Oregon Health and Science University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Ruffell, Brian; Chang-Strachan, Debbie; Chan, Vivien et al. (2014) Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell 26:623-37
Affara, Nesrine I; Ruffell, Brian; Medler, Terry R et al. (2014) B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas. Cancer Cell 25:809-21
Broz, Miranda L; Binnewies, Mikhail; Boldajipour, Bijan et al. (2014) Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26:638-52
Anand, Sudarshan; Coussens, Lisa M (2014) Manipulating microRNAs to regulate macrophage polarization in gliomas. J Natl Cancer Inst 106:
Krummel, Matthew F; Friedman, Rachel S; Jacobelli, Jordan (2014) Modes and mechanisms of T cell motility: roles for confinement and Myosin-IIA. Curr Opin Cell Biol 30:9-16
Gunderson, Andrew J; Coussens, Lisa M (2013) B cells and their mediators as targets for therapy in solid tumors. Exp Cell Res 319:1644-9
Palucka, Karolina; Coussens, Lisa M; O'Shaughnessy, Joyce (2013) Dendritic cells, inflammation, and breast cancer. Cancer J 19:511-6
Ruffell, Brian; Affara, Nesrine I; Cottone, Lucia et al. (2013) Cathepsin C is a tissue-specific regulator of squamous carcinogenesis. Genes Dev 27:2086-98
Ganesan, Anusha-Preethi; Johansson, Magnus; Ruffell, Brian et al. (2013) Tumor-infiltrating regulatory T cells inhibit endogenous cytotoxic T cell responses to lung adenocarcinoma. J Immunol 191:2009-17