The immune system includes a subpopulation of CD8 + T cells equipped to inhibit the expansion of follicular T helper (T FH ) cells, resulting in suppression of autoantibody production and associated lupus-like disease. These CD8 + T regulatory (Treg) cells recognize Qa-1/peptide complexes on target T FH cells and depend on the IL-15 cytokine for development and function. Here we show that these CD8+ Treg cells express a triad of surface receptors-CD44, CD122, and the class I MHC receptor Ly49-and account for <5% of CD8 + T cells. Moreover, the development of systemic lupus erythematosus-like disease in B6-Yaa mutant mice is associated with a pronounced defect in CD8 + Treg cell activity, suggesting that this regulatory subset may represent an effective therapeutic approach to systemic lupus erythematosus-like autoimmune disease.Rag2-deficient mice | cell transfer | HLA-E | KIR | memory CD8 cells
OCT4 is a transcription factor critical for the pluripotency of human embryonal stem (ES) and induced pluipotency stem (IPS) cells. OCT4 is commonly expressed in germ-cell tumors as well as putative cancer stem cells in several tumors, and is a key determinant of oncogenic fate in germ-cell tumors. The capacity of the human immune system to recognize this critical stem-cell gene is not known, but has implications for preventing tumors with ES/IPS-based therapies and targeting stem-cell pathways in cancer. Here we show that OCT4-specific T cells can be readily detected in freshly isolated T cells from most (>80%) healthy donors. The reactivity to OCT4-derived peptides resides primarily in the CD45RO + memory T-cell compartment and consists predominantly of CD4 + T cells. T cells reactive against OCT4-derived peptides can be readily expanded in culture using peptide-loaded dendritic cells. In contrast to healthy donors, immunity to OCT4 was detected in only 35% of patients with newly diagnosed germ-cell tumors. However, chemotherapy of germ-cell tumors led to the induction of anti-OCT4 immunity in vivo in patients lacking such responses at baseline. These data demonstrate the surprising lack of immune tolerance to this critical pluripotency antigen in humans. Harnessing natural immunity to this antigen may allow immune-based targeting of pluripotency-related pathways for prevention of cancers, including those in the setting of ES/IPSbased therapies.
Advanced melanoma is a devastating disease with a very poor overall prognosis. There are only two agents that are approved by the FDA for use in patients with metastatic melanoma: dacarbazine and IL-2. Both agents have an overall response rate well below 20%, with only rare long-term responders noted. Metastatic melanoma is known to be one of the most resistant cancers to a plethora of treatment modalities, such as single-agent and combination chemotherapy, chemoimmunotherapy and immunotherapy with a host of immune stimulators. Indeed, researchers worldwide have recognized the lack of effective therapies and have refocused their efforts on developing novel and cutting-edge strategies of treatment. This is based on an improved understanding of the complex interactions that occur within the tumor microenvironment, and the central role that the host immune system plays in the surveillance of cancer. This review summarizes the recent results of novel immunotherapeutic regimens and focuses on cutting-edge modalities of treatment that encompass new lines of thinking in the war against cancer and, in particular, melanoma.
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