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Tumor-infiltrating immune cells play a key role against cancer. However, malignant cells are able to evade the immune response and establish a very complex balance in which different immune subtypes may drive tumor progression, metastatization and resistance to therapy. New immunotherapeutic approaches aim at restoring the natural balance and increase immune response against cancer by different mechanisms. The complexity of these interactions and the heterogeneity of immune cell subpopulations are a real challenge when trying to develop new immunotherapeutics and evaluate or predict their efficacy in vivo. To this purpose, molecular imaging can offer non-invasive diagnostic tools like radiopharmaceuticals, contrast agents or fluorescent dyes. These agents can be useful for preclinical and clinical purposes and can overcome [ 18 F]FDG limitations in discriminating between trueprogression and pseudo-progression. This review provides a comprehensive overview of immune cells involved in microenvironment, available immunotherapies and imaging agents to highlight the importance of new therapeutic biomarkers and their in vivo evaluation to improve the management of cancer patients.

The CD95 death receptor plays an important role in several physiological and pathological apoptotic processes involving in particular the immune system. CD95 ligation leads to clustering of the receptor cytoplasmic "death domains" and recruitment of the zymogen form of caspase-8 to the cell surface. Activation of this protease through self-cleavage, followed by activation of downstream effector caspases, culminates in cleavage of a set of cellular proteins resulting in apoptosis with disassembly of the cell. It is very well known that the extracellular region of the CD95 receptor is required for CD95L interaction and that the death domain is necessary for the induction of the apoptotic signaling. Here, we identified and characterized a novel CD95 ligandand death domain-independent oligomerization domain mapping to the NH 2 -terminal extracellular region of the CD95 receptor. In vitro and in vivo studies indicated that this domain, conserved among all soluble CD95 variants, mediates homo-oligomerization of the CD95 receptor and of the soluble CD95 proteins, as well as heterooligomerization of the receptor with the soluble variants. These results offer new insight into the mechanism of apoptosis inhibition mediated by the soluble CD95 proteins and suggest a role of the extracellular oligomerization domain in the regulation of the non-signaling state of the CD95 receptor.Apoptosis is a cell death process that can be elicited by a variety of stimuli, such as growth factor deprivation, ionizing radiation, and other DNA-damaging agents, or by triggering specific cell surface receptors, the death receptors. Death receptors belong to the tumor necrosis factor (TNF) 1 receptor gene superfamily, which is characterized by similar cysteinerich extracellular domains (1). The death receptors TNF-R1 (also called p55 or CD120a), CD95 (also called Fas or Apo-1), DR3 (also called Wsl-1, Apo-3, LARD, or TRAMP), DR4 (also called TRAIL-R1), DR5 (also called Apo-2, TRAIL-R2, TRICK2, or KILLER) (2), and DR6 (3) are also characterized by the presence of a death domain within the cytoplasmic region critical for the initiation of apoptotic signaling (4, 5). Notably, CD95 ligand (CD95L) and CD95 receptor interactions play an important role in the regulation of the immune response and in the control of peripheral B and T cell survival that is critical to the maintenance of immune cell homeostasis (6). This system has also been implicated in maintaining immunoprivilege in the eye and testis (7, 8), attenuating immunosurveillance against certain types of tumors, such as melanoma and hepatocellular carcinoma (9). Moreover, alterations in the control of apoptosis, also mediated by the CD95/CD95L system, are involved in the pathogenesis of several diseases such as Hashimoto thyroiditis (10), fulminant hepatitis (11, 12), and toxic epidermal necrolysis (Lyell's syndrome) (13). Thus, it is particularly interesting to elucidate the mechanisms that regulate CD95 and CD95L interactions.A common feature of the death receptors is that, upon binding to...

A longitudinal study of lymphocytic infiltration in the endocrine pancreas of non-obese diabetic mice was performed to investigate the role of different lymphocyte subsets in the pathogenesis of diabetes. The incidence of insulitis and the percentage of mononuclear cell subsets in the pancreas were evaluated in non-obese diabetic mice of various ages (5, 9, 13, 17, 22, 29 and 36 weeks). Cryostat sections of pancreas were stained with heamatoxilin-eosin or with different monoclonal antibodies against total T lymphocytes, helper T lymphocytes, cytotoxic/suppressor T lymphocytes, activated interleukin 2 receptor positive lymphocytes and B lymphocytes. A monoclonal antibody against Class-II antigens was also used. Positive cells were revealed by the immunoperoxidase technique. Insulitis was found in 5 weeks old mice but to a lesser extent than in adult animals. No significant variation between infiltrating cell subsets was found in different age groups. T lymphocytes ranged between 20.4% and 28.1%, B lymphocytes between 28.8% and 30.8% and Class-II positive cells between 22.8% and 32.2%. Interleukin 2 receptor positive cells ranged between 5.5% and 8.5% as detected with AMT-13 monoclonal antibody which recognise the interleukin 2 binding site. A higher percentage of activated cells was observed using another monoclonal antibody (7D4) directed against a different epitope of the interleukin 2 receptor, suggesting the presence of activated lymphocytes with interleukin 2 receptors saturated by interleukin 2. No insulin-containing cells were found to express Class-II molecules as demonstrated by a double immunofluorescence technique. Most infiltrating mononuclear cells were found to be positive for Class-II and L3T4 antigens or to be Class-II positive and express surface immunoglobulins.(ABSTRACT TRUNCATED AT 250 WORDS)