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A Comprehensive Cancer Center Designated by the National Cancer Institute

Select Major Research Findings

Immunology and Cancer

The overall goals of the Immunology and Cancer Program are to understand the interface between the host immune system and malignant tumors and, ultimately, to manipulate that interaction to promote the immune-mediated tumor destruction in patients with cancer. Other program goals include supporting an environment that brings new immunology concepts into preclinical models of anti-tumor immunity, and to translate fundamental discoveries into clinical applications. 

In 2012, Program members produced nearly 40 peer-reviewed publications, many in high-impact journals; 13% are intraprogrammatic efforts, and 28% interprogrammatic collaborations. Highlights of Program members’ research findings are summarized below. These papers were selected to illustrate the program’s expanding efforts in innate immunity, the tumor microenvironment, and translation to the clinic.

Research Highlights

Study reveals functions of ETS1 in natural killer cells
Little is known about the regulatory mechanisms that control the development of natural killer (NK) cells, white blood cells that play a major role in the innate immune system. Barbara Kee, PhD, and colleagues used genome-wide analyses combined with developmental and functional studies to reveal three previously unknown roles for the ETS1 transcription factor in NK cells. They observed that ETS1 directly regulates expression of Idb2 and Tbx21, proteins required for NK cell differentiation; is required for the expression and function of NK cell receptors; and regulates NK cell responsiveness to cytokines. Taken together, these findings provide insight into the critical role of ETS1 in NK cell development and function. (Ramirez et al., Immunity 36:921-32, 2012)
This work was supported by grant numbers CA099978, CA099978-S, GM38663, and CA42014 from the National Institutes of Health.

BTB-ZF factors recruit the E3 ligase cullin 3 to regulate lymphoid effector programs
T- and B-cells play a central role in adaptive immunity by differentiating and acquiring specialized effector functions to protect against microbial infections. Albert Bendelac, MD, PhD, and colleagues examined how promyelocytic leukaemia zinc finger (PLZF), a BTB-zinc finger (BTB-ZF) transcription factor, regulates the differentiation of innate-like natural killer T (NKT)-cell thymocytes. They found that BTB-ZF transcription factors recruit the ubiquitin ligase CUL3 to the cell nucleus, resulting in selective ubiquitination of proteins and regulation of gene expression. According to the researchers, this function is essential for directing the differentiation of several T- and B-cell effector programs, and may also play a role in the development of leukemias and lymphomas. (Mathew et al., Nature 491:618-21, 2012)
This work was supported by National Institute of Health (NIH) grants 5RO1GM082940 and RO1AI038339, and an Irvington Institute postdoctoral fellowship from the Cancer Research Institute.

Cellular and molecular requirements for rejection of B16 melanoma in the setting of regulatory T cell depletion and homeostatic proliferation
Studies have shown that adoptive T cell therapy is useful in generating antitumor immune responses in patients with advanced melanoma. Thomas Gajewski, MD, PhD, Justin Kline, MD, and Kenneth Cohen, MD, (Hematopoiesis and Hematological Malignancies Program) studied the host requirements for melanoma rejection by adoptively transferred Treg-depleted T cells in mice. Their observations support a model in which tumor rejection requires host tumor Ag cross-presentation for priming adoptively transferred T cells, as well as IFN-γ as a central mediator. These findings will facilitate the development of strategies to restore immune-mediated tumor control. (KIine et al., J Immunol 188:2630-42, 2012)
This work was supported by grant number P01 CA97296 from the National Institutes of Health.

Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens 
The mechanisms underlying celiac disease, characterized by dysregulated mucosal immune response to dietary gluten, are largely unknown. Using a mouse model, Bana Jabri, MD, PhD, and Sonia Kupfer, MD (Cancer Prevention and Control Program), discovered that retinoic acid in conjunction with IL-15, a cytokine highly expressed in patients with celiac disease, activates the induction of JNK phosphorylation and downstream release of proinflammatory cytokines by dendritic cells. These findings demonstrate an unexpected role for retinoic acid and IL-15 in the promotion of inflammatory response to gluten. In the cancer context, they imply that local application of IL-15 should be pursued as a therapeutic strategy, to mimic this type of local tissue destruction. (DePaolo et al., Nature 471:220-4, 2011)
This work was supported by the Digestive Disease Research Core Center at the University of Chicago (DK42086), grants R01 DK67180 and R01 DK71003 from the National Institutes of Health, and the Crohn’s and Colitis Foundation.