Francine Jotereau

Evidence for a cyclic renewal of lymphocyte precursor cells in the embryonic chick thymus

Experiments involving sequential transplantations of the chick embryonic thymus at E9 to E12 into a first 3-day host quail embryo and then into a second chick host allowed demonstration of the cyclic periodicity of hemopoietic cell seeding of the embryonic thymus. After a first wave of colonization occurring between E6.5 and E8, the thymus becomes refractory to hemopoietic cell entry for about 4 days. It resumes its capacity to be seeded by a second wave of blood-borne stem cells at E12. After a second period of non receptivity starting at E14, a third wave of incoming cells reaches the thymus around E18. Therefore, with a slightly different periodicity, the same cyclic mechanism regulates the renewal of lymphocytes in chick and quail embryos. Quail hemopoietic cells were immunostained in the chimeric thymuses, with a species specific monoclonal antibody (anti-MB1) which recognizes a common surface antigenic determinant on all endothelial and blood cells of the quail (except erythrocytes). Two steps could thus be distinguished in the seeding process. When the thymus becomes receptive for hemopoietic cells, the latter first accumulate in the intrathymic blood vessels before penetrating massively in the thymic parenchyma. The quail chick-chimera system combined with the use of a species- and cell-type-specific antibody provides a unique tool for studying thymic colonization by lymphocyte precursors.

CD4CD8αα Lymphocytes, A Novel Human Regulatory T Cell Subset Induced by Colonic Bacteria and Deficient in Patients with Inflammatory Bowel Disease

Gut bacterium Faecalibacterium prausnitzii activates a newly identified set of human IL-10-producing Treg cells (CD4CD8αα lymphocytes), revealing a mechanism by which commensal microbes contribute to host immunity.

An additional ORF on meloe cDNA encodes a new melanoma antigen, MELOE-2, recognized by melanoma-specific T cells in the HLA-A2 context.

We characterized a new melanoma antigen derived from one of the multiple open reading frames (ORFs) of the meloe transcript. The meloe gene is overexpressed in melanomas as compared to other cancer cell lines and normal tissues. The corresponding transcript is rather unusual, in that it does not contain a long unique ORF but multiple short ORFs. We recently characterized a tumor epitope derived from a polypeptide (MELOE-1) encoded by the ORF1230–1370 and involved in relapse prevention of melanoma patients treated with autologous tumor infiltrating lymphocytes (TIL). Here we show that the ORF285–404 encodes a polypeptide called MELOE-2 that also generated a HLA-A2 epitope recognized by a melanoma-specific T cell clone derived from the same TIL population from which we derived the MELOE-1-specific T cell clone. We also showed that HLA-A2 melanoma cells were spontaneously recognized by the MELOE-2-specific T cell clone, and we detected the presence of MELOE-2 reactive T cells in another TIL population infused to a patient who remained relapse-free after TIL treatment. These results demonstrate that translation of meloe transcript in melanoma cells can produce at least two immunogenic polypeptides, MELOE-1 and MELOE-2, from two distinct ORFs that could be relevant target for melanoma immunotherapy.

Abstract SY40-02: Interplay between microenvironment and cancers

Tumors are highly adept at evading the immune system through a multitude of mechanisms, including the secretion of factors that modulate both innate and adaptive immunity. Matrix metalloproteinase-2 (MMP-2) is a proteolytic enzyme that degrades the extracellular matrix and is over expressed by many tumors, including melanoma. We recently documented the presence of MMP-2-specific CD4(+) T cells in tumor-infiltrating lymphocytes (TILs) in several melanoma patients (Cancer Cell 19:333, 2011). Strikingly, MMP-2-specific CD4(+) T cells displayed an inflammatory T(H)2 profile, mainly TNF-α, IL-4, and IL-13 and expressing GATA-3. When exposed to MMP-2, immature human dendritic cells (DCs) primed naive CD4(+) T cells to differentiate into an inflammatory T(H)2 phenotype through OX40L expression and inhibition of IL-12p70 production. MMP-2 was subsequently found to degrade the type I IFN receptor, thereby preventing STAT1 phosphorylation, which is necessary for IL-12p35 production, and the subsequent formation of bioactive IL-12. More recently we have explored the mechanisms underlying the up regulation of OX40L and have identified signaling pathways and potential receptors that lead to this modulation. Active MMP-2, therefore, acts as an endogenous type 2 “conditioner” providing an explanation for the observed prevalence of detrimental type 2 responses in melanoma. Novel properties of MMP-2 on other components of the immune system, and on tumor progression, will be discussed along with DC-based strategies to alleviate immune suppression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY40-02. doi:1538-7445.AM2012-SY40-02