Angiogenic processes depend on the precise coordination of different cell types and a complex exchange of signals, many of which derive from new specific components of the provisional, angiogenesisrelated, extracellular matrix (ECM). Angiogenesis-associated ECM components thus represent appealing targets for the selective delivery of therapeutic molecules to newly forming tumor vessels. Results of a previous study indicated that a high affinity recombinant antibody (L19) to ED-B, a domain contained in the angiogenesis-associated isoform of fibronectin (B-FN), selectively and efficiently targets tumor vessels. The present study shows that a fusion protein between L19 and interleukin 2 (L19-IL-2) mediates the selective delivery and concentration of IL-2 to tumor vasculature, thereby leading to a dramatic enhancement of the therapeutic properties of the cytokine. By contrast, IL-2 fused to an irrelevant recombinant antibody used as a control fusion protein showed neither accumulation in tumors nor therapeutic efficacy. Tumors in mice treated with L19-IL-2 were significantly smaller compared to those in animals treated with saline, the control fusion protein, or IL-2 alone (P ؍ .003, .003, and .002, respectively). Moreover, no significant differences in size were observed among the tumors from the different control groups (using the control fusion pro- IntroductionDuring tumor progression, the extracellular matrix (ECM) of the normal tissues in which the tumor grows is remodeled through 2 different processes: proteolytic degradation and neosynthesis of ECM components by both neoplastic and stromal cells. These processes generate a "tumoral ECM" that differs quantitatively and qualitatively from the normal tissue ECM and that apparently gives rise to a more suitable environment (inductive or instructive) for tumor progression. [1][2][3] In particular, ECM components modulate vascular cell behavior and angiogenic processes. 4,5 This observation is upheld by the recent report that the majority of messenger RNAs (mRNAs) newly expressed by tumoral endothelial cells encode for ECM proteins. 6 Thus, these provisional ECM components that appear during the angiogenic processes represent an appealing target for the selective delivery of therapeutic molecules to newly forming blood vessels. 7 Furthermore, because new vessel formation is common to all solid tumors, the angiogenesisassociated ECM components can be regarded as pan-tumoral antigens. [8][9][10][11][12] One such ECM component is a fibronectin (FN) isoform, B-FN, which contains an extra FN type III repeat of 91 amino acids, the domain B (ED-B). 13 Because the amino acid sequence of ED-B is identical in mouse, humans, and other mammals, antibodies to this domain react equally well with mouse, human, and other species B-FN. B-FN is detectable only in the stroma of fetal and neoplastic tissues and around newly forming blood vessels, but not in mature vessels. 14,15 Using a radioiodinated human recombinant single-chain Fv (scFv; L19) to the ED-B domain of FN, we demon...
The HIV-1 Tat protein is a potent chemoattractant for monocytes. We observed that Tat shows conserved amino acids corresponding to critical sequences of the chemokines, a family of molecules known for their potent ability to attract monocytes. Synthetic Tat
Uveal melanoma (UM), a rare cancer of the eye, is distinct from cutaneous melanoma by its etiology, the mutation frequency and profile, and its clinical behavior including resistance to targeted therapy and immune checkpoint blockers. Primary disease is efficiently controlled by surgery or radiation therapy, but about half of UMs develop distant metastasis mostly to the liver. Survival of patients with metastasis is below 1 year and has not improved in decades. Recent years have brought a deep understanding of UM biology characterized by initiating mutations in the G proteins GNAQ and GNA11. Cytogenetic alterations, in particular monosomy of chromosome 3 and amplification of the long arm of chromosome 8, and mutation of the BRCA1-associated protein 1, BAP1, a tumor suppressor gene, or the splicing factor SF3B1 determine UM metastasis. Cytogenetic and molecular profiling allow for a very precise prognostication that is still not matched by efficacious adjuvant therapies. G protein signaling has been shown to activate the YAP/TAZ pathway independent of HIPPO, and conventional signaling via the mitogen-activated kinase pathway probably also contributes to UM development and progression. Several lines of evidence indicate that inflammation and macrophages play a pro-tumor role in UM and in its hepatic metastases. UM cells benefit from the immune privilege in the eye and may adopt several mechanisms involved in this privilege for tumor escape that act even after leaving the niche. Here, we review the current knowledge of the biology of UM and discuss recent approaches to UM treatment.
Natural killer (NK) cells express surface receptors for defined groups of HLA class I alleles. The specific interaction between these receptors and HLA class I molecules expressed on target cells results in inhibition of NK-mediated target cell lysis. In this report, we analyzed whether similar mechanisms were operating in cytolytic T lymphocytes (CTLs) capable of lysing NK-sensitive target cells. T cell clones were screened for their ability to lyse K562 target cells. The selected clones expressed either gamma delta or alpha beta TCR. The majority of these clones failed to lyse the HLA class I+ R8/15375 cell line; however, upon addition of the previously described A6-136 (IgM) or 6A4 F(ab')2 anti-HLA class I mAbs, target cells were efficiently lysed. Lysis of autologous phytohemagglutinin blasts in the presence of anti-HLA class I mAbs occurred primarily with TCR gamma delta+ CTLs. Recognition of HLA class I molecules on target cells implies the expression of NK-related specific receptors in CTL clones. Indeed, phenotypic analysis of > 300 CTL clones with NK-like activity revealed that 28% expressed p58 molecules (specific for HLA-C alleles) while 30% expressed CD94 molecules (specific for the Bw6 specificity). These receptor molecules were found to function as inhibitory receptors, as revealed by the effect of anti-p58 or anti-CD94 mAbs (of IgG isotype) on the lysis of the Fc gamma R+ K562 target cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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