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Acute lymphoblastic leukemia (ALL) is the most frequentchildhood malignancy. Although it is well established that geneticabnormalities are critical for the development of ALL, the mechan-ismsthatconferaselectiveadvantagetotheleukemiacellsintheirsiteof origin, the bone marrow (BM), are largely unknown. The inter-actionsofALLblastswithBMstromalcellshaveapositiveimpactonleukemia cell survival and resistance to chemotherapy. ALL stimu-lates BM stromal cells, which reciprocally promote leukemia cellsurvival [1–7]. In addition, it is conceivable that leukemic cellspromote a microenvironmental change in the BM so as to inhibitnormal hematopoiesis.The interaction between ALL and BM stromal cells occurs inspecific cell niches, characterized by the expression of moleculessuchasE-selectinandstromal-cell-derivedfactor1(SDF-1)[8].BMniches are critical in sustaining ALL cell survival [9]. Close associ-ation of ALL to bone marrow stromal cells is important for ALLsurvivalinvitro.Adhesionisinpartmediatedbyb1integrins(VLA4and VLA5) and CD44, expressed on leukemia cells, and the fibro-nectinandvascularcelladhesionmolecule-1(VCAM-1),expressedonthestromallayer[2–4].InteractionwiththestromalVCAM-1celladhesion molecule renders VLA-4þleukemic cell lines resistant toAra-CandVP-16(etoposide)[10].BMStromalcellsproduceseveralgrowth factors [11,12]; some may provide a microenvironmentsuitable for leukemogenesis and leukemic progression. SDF-1,Interleukin-3 (IL-3), IL-7, stem cell factor (SCF), and FMS-liketyrosine kinase 3 ligand (Flt3-L) alone or in different combinationswere shown to promote the survival and or proliferation of B-cellprecursor ALL cells cultured onto BM stromal layers, although thedegreeofstimulationisheterogeneous betweenpatientsamplesandbetween growth factors [13–16]. Levels of basic fibroblast growthfactor (bFGF), hepatocytegrowth factor (HGF), and tumor necrosisfactor-a(TNF-a)aresignificantlyhigherinperipheralbloodplasmasamples frompatients withALL comparedwithhealthy controls, inassociation with increased angiogenesis [17]. The leukemic BMplasma contains increased levels of bFGF, and vascular endothelialfactor (VEGF) levels are increased in some patients [7]. Theabnormally high levels of these growth factors are able to promoteangiogenesis [7], and in some cases may directly benefit ALL cells.Forinstance,VEGFproducedbystromalcellsstimulatesBcl-2phos-phorylation and resistance of ALL cell lines to different chemo-therapeutic agents [18].

Follicular lymphomas (FLs) localize in lymphoid tissues and recapitulate the structure of normal secondary follicles. The chemokine/chemokine receptor pair CXCL13/CXCR5 is required for the architectural organization of B cells within lymphoid follicles. In this study, we showed that CXCL13 was secreted by FL cells. FL cells expressed CXCR5 and migrated in response to CXCL13. Furthermore, we observed a synergistic effect between CXCL13 and CXCL12 (SDF-1), a chemokine produced by stromal cells in lymphoid tissues. The production of CXCL13 by FL cells and CXCL12 by stromal cells probably directs and participates in the accumulation of FL cells within specific anatomic sites.

The localization and establishment of follicular lymphoma (FL) cells in distinct anatomic sites probably involves chemokine and adhesion receptors on the neoplastic cells and appropriate chemokines and adhesion receptor ligands in the microenvironment. Several chemokines play an important role in normal B-cell trafficking and differentiation. Monocyte chemoattractant protein-1 (MCP-1) is a C-C chemokine that induces chemotaxis of a variety of lymphoid cells through its receptor CCR2. CCR2 is also expressed on B cells, and MCP-1 induces chemotaxis of normal B cells. In this report, we investigated expression and function of CCR2 on FL cells. We found FL cells as well as the t(14; 18)+ B-cell lymphoma line H2 expressed CCR2. MCP-1 potentiated SDF-1-induced chemotaxis of FL cells and H2 cells, but MCP-1 alone did not induce chemotaxis. The specificity of the effects of MCP-1 and SDF-1 was demonstrated by antibody blocking studies. Because FL cells are generally associated with follicular dendritic cells (FDCs), FDCs may be an important source of chemokines. We found that cultured FDCs produced MCP-1, and this production was enhanced by tumour necrosis factor. These data implicate MCP-1 in the migration and localization of FL cells.

HER-2/neu is a tumor-associated antigen overexpressed in a large variety of human tumors. Eight HER-2/neu peptides displaying HLA-A*0201 anchoring motifs were selected and tested for their binding affinity to HLA-A*0201 and their capacity to elicit cytotoxic T lymphocyte (CTL) responses in both HLA-A*0201 transgenic mice and in HLA-A*0201(+) healthy donors. Two high-affinity (p5 and p48) and one intermediate-affinity (p1023) peptides triggered CTL responses in both transgenic mice and humans, comparable to those observed for the well-known HER2/neu dominant peptide p369. CTL induced in transgenic mice lysed HLA-A*0201(+) RMA cells infected with recombinant HER-2/neu but not cells infected with wild-type vaccinia virus. Human CTL lysed HLA-A*0201(+) HER-2/neu(+) tumor cells of different origins (breast, colon, lung and renal cancer) irrespective of the expression levels of HER-2/neu. Importantly, primed CTL specific for these epitopes were detected in freshly isolated tumor-infiltrating lymphocytes from three renal cell carcinoma patients. Therefore, the HER-2/neu peptides p5, p48 and p1023 may be good candidates for immunotherapy of a broad spectrum of tumors, including renal cell carcinoma.