Cancer Immunology: Major Accomplishments
Investigators in the Cancer Immunology Program generated 127 publications in 2010. Major achievements include the following:
The Dustin and Lafaille labs have engaged in an intra-programmatic collaboration that is providing insight into signaling pathways in regulatory T cells (Treg) that control functional programs, and may identify targets to suppress Treg function to enhance cancer immunotherapy. While PKC-q activation is a positive signaling pathway for conventional T cells, its activation reduces the activity of Treg cells. Work in progress has identified a distinct activating pathway based on utilization of an alternative membrane-associated quanylate kinase (MAGUK). PKC-q phosphorylates the MAGUK Card11 (Carma1) to activation the NF-ƘB family of transcription factors. In Treg, the activation of PKC-q and Card11 is associated with a specific organelle distal from the immunological synapse. Relatively little PKC-q or Card11 is recruited to the immunological synapse.
The Littman and Lafaille labs have discovered that derivatives of the plant cardiac glycoside digoxin that lack cardiac toxicity can inhibit the development of pro-inflammatory Th17 T cells by inhibiting the function of RORgt. Th17 cells have a role in autoimmune diseases, and these compounds reduced the incidence of experimental autoimmune encephalomyelitis -- the mouse model of multiple sclerosis. Inflammation caused by Th17 cells may also contribute to cancer progression, suggesting that the ability to manipulate Th17 cells will be important for cancer prevention and immunotherapy efforts.
Miller and Frey have studied myeloid-derived suppressor cell expansion in the livers of mice with abdominal adenocarcinoma. They found that the expansion of CD11b+Gr1+ cells in the liver depends upon the expression of chemokine KC by tumor cells. This resulted in a preclinical mouse model suggesting that targeting KC may reduce liver metastases in abdominal adenocarcinoma.
The Cho and Bhardwaj labs have engaged in an intra-programmatic collaboration to determine the degree of cellular and humoral responses to type I melanoma antigen genes (MAGE) in patients with plasma cell dyscrasias such as multiple myeloma (MM). They found that half of MM patients have cellular and humoral responses to CT7 (MAGE-C1), and a lower frequency have antibody titers against MAGE-A1 and the related antigen SSX1. These results support the notion that MAGE are immunogenic and should be considered further for therapeutic cancer vaccines.
In another inter-programmatic collaboration, the Newcomb, Zagzag, Demaria, and Formenti labs have demonstrated synergy between radiation therapy and anti-CD137-based immunotherapy for glioma. The combination was effective in prolonging survival of 6 of 9 mice with stereotactically implanted gliomas. These results support the initiation of clinical trials combining radiation therapy with anti-CD137 costimulatory immunotherapy.
The Dustin and Demaria labs have made further progress on a National Cancer Institute-funded collaboration to understand the mechanism of synergy between local radiation therapy and anti-CTLA-4 treatment to shrink an implanted breast carcinoma, 4T1. In a recent breakthrough, scientists now have direct evidence that NKG2D contributes to tumor growth inhibition with this combined therapy. These new data demonstrate the biological significance of NKG2D-assisted immunological synapses in primary tumor shrinkage and the reduction of metastatic disease.
Lymphocyte Biology and Oncogenesis
The Aifantis lab and the Genomics Core have used whole genomic approaches to determine the impact of the Fbw7 ubiquitin ligase action on its substrate, c-Myc, in adult and embryonic stem cells differentiation. Fbw7 controls the stability of c-Myc, which was critical in controlling stem cell quiescence through multiple transcriptional targets. Understanding the regulation of the c-Myc protooncogene is critical for understanding its role in cancer and cancer stem cells.