01 - Cancer Biology & Immunology

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ABSTRACT – CANCER BIOLOGY AND IMMUNOLOGY (CBI) PROGRAM Overview and Goals: The goals of the Cancer Biology and Immunology (CBI) program are to identify basic mechanisms of cancer cell biology and the immune response in order to develop novel therapeutic approaches to treat cancer. In particular, CBI members are interested in the transcriptional and epigenetic mechanisms controlling tumor and immune cell function, the impact of metabolism and metabolites on tumor and immune cell biology, and the role of the microenvironment in tumor biology and immune activity. Research Highlights: CBI investigators recently showed that the CXCL12/CXCR4 axis is an important target in both Acute Myeloid Leukemia (AML) and Chronic Myeloid Leukemia (CML). Targeting CXCR4 on AML promotes oxidative stress and terminal differentiation of leukemic stem cells (Cell Rep. 20201), whereas blockade of CXCL12 combined with tyrosine kinase inhibitors eliminates CML stem cells (Cell Stem Cell 20192). CBI investigators also defined how metabolites influence tumor and immune cell activities: tumor-derived L-2-hydroxyglutarate influences renal cancer progression and prognosis (Clin. Cancer Res. 20183), and alpha-ketoglutarate regulates the differentiation and function of CD4 T cells (Immunity 20174). Mechanistic discoveries by CBI investigators have led to therapeutics that are now being tested in clinical trials, including a heparanase inhibitor for multiple myeloma (Haematologica 20185) and a DNMT1 inhibitor for MDS and AML (NCT04167917). Program Activities: CBI catalyzes intra- and inter-programmatic interactions via monthly meetings, annual retreats, and seminars. Technology forums introduce members to new and existing capabilities of the Shared Resources, and members' discoveries are advanced from the bench to Phase I clinical trials through pilot funding from the Alabama Drug Discovery Alliance and the O'Neal Invests program. Members: CBI has 57 members from 16 Departments/Divisions who have a combined $5.2M in NCI funding and $10.1M in total cancer-relevant, peer- reviewed grants. In the current cycle, CBI members published 693 cancer-relevant publications, of which 39% were inter-programmatic and 23% were intra-programmatic collaborations and 18% of which are in journals with impact factor of 9 or greater. Future Directions: In line with the O'Neal strategic plan, CBI will focus on the role of obesity and metabolism in regulating cancer progression and the anti-tumor immune response. Of the 13 cancers linked with obesity, CBI investigators already have strength in tumor biology and anti-tumor immunity in multiple myeloma, renal, breast, and ovarian cancers, and we expect that these efforts will lead to collaborative, multi-PI grants in the next funding period. These cancers overlap with those being targeted by our Community Outreach and Engagement office, in part due to their relevance to the catchment area. Finally, CBI members will leverage imaging techniques developed by ET to follow tumor cell activity and immune cell reactivity in situ.