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Targeting tyrosine kinase receptors (RTKs) with specific Abs is a promising therapeutic approach for cancer treatment, although the molecular mechanism(s) responsible for the Abs' biological activity are not completely known. We targeted the transmembrane RTK for hepatocyte growth factor (HGF) with a monoclonal Ab (DN30). In vitro, chronic treatment of carcinoma cell lines resulted in impairment of HGF-induced signal transduction, anchorage-independent growth, and invasiveness. In vivo, administration of DN30 inhibited growth and metastatic spread to the lung of neoplastic cells s.c. transplanted into immunodeficient nu͞nu mice. This Ab efficiently down-regulates HGF receptor through a molecular mechanism involving a double proteolytic cleavage: (i) cleavage of the extracellular portion, resulting in ''shedding'' of the ectodomain, and (ii) cleavage of the intracellular domain, which is rapidly degraded by the proteasome. Interestingly, the ''decoy effect'' generated by the shed ectodomain, acting as a dominant negative molecule, enhanced the inhibitory effect of the Ab.Ab ͉ metastasis ͉ tyrosine kinase ͉ receptor degradation ͉ proteolytic cleavage

The natural history of B‐chronic lymphocytic leukemia (CLL) is not entirely explained by intrinsic defects of the neoplastic cell, but is also favored by microenvironmental signals. As CLL cells retain the capacity to respond to CD40 ligand (CD40L) and as CD4+ T cells are always present in involved tissues, we asked whether malignant CLL cells might produce T cell‐attracting chemokines. We studied the chemokine expression of CD19+/CD5+ malignant B cells from peripheral blood (PB), lymph nodes (LN) or bone marrow (BM) of 32 patients and found a major difference. LN‐ and BM‐, but not PB‐derived cells, expressed a readily detectable reverse transcription‐PCR band for CCL22 and one for CCL17 of variable intensity. CD40 ligation of PB cells induced the mRNA expression of both CCL22 and CCL17. CCL22 was also released in the culture supernatants. These supernatants induced the migration of activated CD4+, CD40L+ T cells expressing the CCL22 receptor, CCR4. T cell migration was abrogated by anti‐CCL22 antibodies. Immunohistochemistry and cytofluorography studies revealed that a proportion of CD4+ T cells in CLL LN and BM expressed CD40L. Our data demonstrate that malignant CLL cells chemo‐attract CD4+ T cells that in turn induce a strong chemokine production by the leukemic clone, suggesting a vicious circle, leading to the progressive accumulation of the neoplastic cells.

Growth and survival of chronic B-cell tumors are favored by the malignant cell's capacity to respond to selected microenvironmental stimuli provided by nontumoral bystander cells. To investigate which mechanisms operate in these crosstalks and whether they are malignancy-related or reproduce the mechanisms used by normal B cells we have studied the expression and functional role of semaphorin CD100 (now called Sema4D) in chronic lymphocytic leukemia (CLL) cells and normal CD5 ؉ B cells.We demonstrate here that (1) leukemic and normal CD5 ؉ B lymphocytes uniformly express CD100; (2) the CD100 highaffinity receptor Plexin-B1 is expressed by bone marrow stromal cells, follicular dendritic cells, and activated T lymphocytes, and is thus available to CD100 ؉ lymphocytes in different specific microenvironments; and (3) upon interaction between CD100 and Plexin-B1 both CLL and normal CD5 ؉ B cells increase their proliferative activity and extend their life span. These findings establish that Plexin-B1 is an easily accessible receptor for CD100 within the immune system. The encounter of CD100 ؉ leukemic cells with Plexin-B1 may promote the proliferation and survival of malignant cells. The crosstalk operated by the CD100/ Plexin-B1 interaction is not malignancy related but reproduces a mechanism used by normal CD5 ؉ B

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Cancer-related mortality can be decreased by prevention, early detection and improved therapies. Although animal models should be used to evaluate the success of cancer therapies, their usefulness is controversial. Many cancer therapies that have cured tumors in mice have not met with similar success when attempted in humans. Current animal models rely mainly on inoculating cell lines into animals, a method that does not reproduce the natural development of the tumor, both for the kinetics of induction and the anatomical site concerned. In this study, we have used an SV40 T-antigen-transgenic mouse model of prostate cancer in which the tumor spontaneously develops orthotopically with a disease progression that closely resembles the progression of human prostate cancer. We have used this model to test the suitability of adoptive cellular immunotherapy. Transfer of naive cells obtained from a T-antigen-negative congenic animal had significant but partial effects: it prevented development of malignant tumors, leaving just minor foci of residual tumor and/or hyperplasia. Adoptive transfer of memory lymphocytes specific for T-antigen, which is a prostatic self antigen in this model, prevented tumor development and progression without affecting the morphology and function of involved tissues. Treated animals were able to breed, and their survival was greatly increased. These results strongly suggest that adoptive immunotherapy should be successful in treating early stages of human prostate cancer.

The recombinase-activating genes, RAG-1 and RAG-2, can be expressed by a subset of B cells within germinal centers, where they mediate secondary V(D)J rearrangements. This receptor revision mechanism could serve either receptor diversification or tolerance-induced functions. Alternatively, it might rescue those cells the receptors of which have been damaged by somatic mutation. Less is known about the occurrence of similar mechanisms in T cells. Here we show that mature T cells with defective TCR surface expression can express RAG genes and are capable of initiating secondary V(D)J rearrangements. The possibility that a cell rescue mechanism based on the generation of a novel Ag receptor might be active in peripheral T cells is envisaged.