OREGA Biotech (France)

Psoriasis is a frequent inflammatory disease that involves mostly the skin and sometimes the joints. This chronic disease is rarely life-threatening but impairs significantly the patient's quality of life. It is characterized, in its typical form, by erythematous and squamous plaques with well-defined borders, associated with increased proliferation of the keratinocytes, inflammation and greater number of dilated blood vessels in the upper dermis. A role of Th1 CD4 T cells was initially suspected. More recently, Th17 CD4 T cells have been shown to play a major role in the disease. It has led to the development of Th17 inhibitors, such as anti-IL-23 (cytokine that induces Th17 CD4 T cell differentiation), anti-IL-17, anti-IL-17RA (IL-17 receptor) and anti-IL-22 (cytokines that are notably produced by Th17 CD4 T cells).

Cancer stem cells (CSC) were first identified in leukemia, and evidence accumulates for their relevance in various solid tumors as well. CSCs are attractive targets for cancer therapy because they sustain tumor growth and may participate to resist therapy and metastatic dissemination. Our knowledge in the field of cancer stem cell biology is progressively increasing. Recently, it has been demonstrated that CSCs can arise from differentiated, non-tumorigenic tumor cells lacking self-renewal properties through Epithelial to Mesenchymal Transition (EMT). In fact, this trans-differentiation process is suspected to confer extreme phenotypic plasticity to cancer cells that can spontaneously switch from the non-stem cell to the stem cell compartment, and vice versa. Here, I review recent literature in the field and discuss potential implications for cancer patients and the design of future therapies.

The proinflammatory cytokine Interleukin 17A (hereafter named IL–17A) or IL-17A producing cells are elevated in breast tumors environment and correlate with poor prognosis. Increased IL-17A is associated with ER(−) or triple negative tumors and reduced Disease Free Survival. However, the pathophysiological role of IL-17A in breast cancer remains unclear although several studies suggested its involvement in cancer cell dissemination. Here we demonstrated that a subset of breast tumors is infiltrated with IL-17A-producing cells. Increased IL-17A seems mainly associated to ER(−) and triple negative/basal-like tumors. Isolation of tumor infiltrating T lymphocytes (TILs) from breast cancer biopsies revealed that these cells secreted significant amounts of IL-17A. We further established that recombinant IL-17A recruits the MAPK pathway by upregulating phosphorylated ERK1/2 in human breast cancer cell lines thereby promoting proliferation and resistance to conventional chemotherapeutic agents such as docetaxel. We also confirmed here that recombinant IL-17A stimulates migration and invasion of breast cancer cells as previously reported. Importantly, TILs also induced tumor cell proliferation, chemoresistance and migration and treatment with IL-17A-neutralizing antibodies abrogated these effects. Altogether these results demonstrated the pathophysiological role of IL-17A-producing cell infiltrate in a subset of breast cancers. Therefore, IL-17A appears as potential therapeutic target for breast cancer.

Regulatory T (Treg) cells can balance normal tissue homeostasis by limiting inflammatory tissue damage, e.g. during pathogen infection, but on the other hand can also limit protective immunity induced during natural infection or following vaccination. Because most studies have focused on the role of CD4(+) Treg cells, relatively little is known about the phenotype and function of CD8(+) Treg cells, particularly in infectious diseases. Here, we describe for the first time the expression of CD39 (E-NTPDase1) on Mycobacterium-activated human CD8(+) Tcells. These CD8(+) CD39(+) Tcells significantly co-expressed the Treg markers CD25, Foxp3, lymphocyte activation gene-3 (LAG-3), and CC chemokine ligand 4 (CCL4), and suppressed the proliferative response of antigen-specific CD4(+) T helper-1 (Th1) cells. Pharmacological or antibody mediated blocking of CD39 function resulted in partial reversal of suppression. These data identify CD39 as a novel marker of human regulatory CD8(+) Tcells and indicate that CD39 is functionally involved in suppression by CD8(+) Treg cells.