Integrin VLA-4 Research Articles

VLA-4 Induces Chemoresistance of T Cell Acute Lymphoblastic Leukemia Cells via PYK2-Mediated Drug Efflux

Simple SummaryCellular adhesion plays an important role in the development of resistance to chemotherapy (chemoresistance) that represents a major hurdle in the treatment of leukemia and which is a major cause for patient relapse. In this study, we evaluated if cell adhesion to the molecule VCAM-1, which is present in the leukemia microenvironment, can favour the chemoresistance of T acute lymphoblastic leukemia (T-ALL). Our results showed that adhesion of T-ALL cells to VCAM-1 via their receptor VLA-4 induces the resistance of T-ALL cells to doxorubicin by activating the signaling protein PYK2 but not FAK. VLA-4/PYK2 signaling did so by inducing the efflux of doxorubicin. However, adhesion of T-ALL cells to fibronectin via the receptor VLA-5 did not activate PYK2 and had no effect on doxorubicin resistance. These findings suggest that targeting the VLA-4/PYK2 pathway could overcome T-ALL chemoresistance and reduce the risk of patient relapse.Cell adhesion plays a critical role in the development of chemoresistance, which is a major issue in anti-cancer therapies. In this study, we have examined the role of the VLA-4 integrin, a major adhesion molecule of the immune system, in the chemoresistance of T-ALL cells. We found that attachment of Jurkat and HSB-2 T-ALL cells to VCAM-1, a VLA-4 ligand, inhibits doxorubicin-induced apoptosis. However, their adhesion to fibronectin, which is mainly mediated via VLA-5, had no effect. Even the presence of the chemoattractant SDF1α (Stromal cell-derived factor-1α), which enhances the adhesion of T-ALL cells to fibronectin, did not modify the sensitivity of the cells attached on fibronectin towards doxorubicin-induced apoptosis. Mechanistically, we found that VLA-4 promoted T-ALL chemoresistance by inducing doxorubicin efflux. Our results showed that cell adhesion to both fibronectin and VCAM-1-induced Focal adhesion kinase (FAK) phosphorylation in T-ALL cells. However, only cell adhesion to VCAM-1 led to PYK2 phosphorylation. Inhibition studies indicated that FAK is not involved in doxorubicin efflux and chemoresistance, whereas PYK2 inhibition abrogated both VLA-4-induced doxorubicin efflux and chemoresistance. Together, these results indicate that the VLA-4/PYK2 pathway could participate in T-ALL chemoresistance and its targeting could be beneficial to limit/avoid chemoresistance and patient relapse.

Plasma cells Dynamics in the Bone Marrow Niche

Abstract Plasma cells (PCs) can become long-lived with age to maintain prophylactic antibody titer for decades in the bone marrow (BM) microenvironment that are enriched in supporting chemokines and pro-survival cytokines. It has been that PCs are sessile in the BM to receive various pro-survival signals, but how they access these signals in the dynamic BM microenvironment remains unknown. Here by establishing long-term intravital imaging of the mouse tibial BM, we show that PCs are overall motile within the BM parenchyma with unique intermittent and heterogenous motility over time. Their motility is reduced when they are in clusters or as they enter a cluster. PC cluster formation and motility requires the pro-survival cytokine APRIL. PCs motility also requires the chemokine receptor CXCR4 and its ligand CXCL12 that are known important for PC homing to BM. CXCR4/CXCL12 signaling-triggered integrin VLA-4 activation negatively regulates PC motility in the BM. Notably, not only do PCs migrate within the BM parenchyma, but they can also egress and recirculate under steady state condition or CXCR4 and VLA4 inhibition. PC motility, clustering, and recirculation are all increased with mouse age. Thus, PC motility and cluster formation underlie a dynamic BM survival niche, contributing to PC longevity and function.

Functional Mapping of Adhesiveness on Live Cells Reveals How Guidance Phenotypes Can Emerge From Complex Spatiotemporal Integrin Regulation.

Immune cells have the ubiquitous capability to migrate disregarding the adhesion properties of the environment, which requires a versatile adaptation of their adhesiveness mediated by integrins, a family of specialized adhesion proteins. Each subtype of integrins has several ligands and several affinity states controlled by internal and external stimuli. However, probing cell adhesion properties on live cells without perturbing cell motility is highly challenging, especially in vivo. Here, we developed a novel in vitro method using micron-size beads pulled by flow to functionally probe the local surface adhesiveness of live and motile cells. This method allowed a functional mapping of the adhesiveness mediated by VLA-4 and LFA-1 integrins on the trailing and leading edges of live human T lymphocytes. We show that cell polarization processes enhance integrin-mediated adhesiveness toward cell rear for VLA-4 and cell front for LFA-1. Furthermore, an inhibiting crosstalk of LFA-1 toward VLA-4 and an activating crosstalk of VLA-4 toward LFA-1 were found to modulate cell adhesiveness with a long-distance effect across the cell. These combined signaling processes directly support the bistable model that explains the emergence of the versatile guidance of lymphocyte under flow. Molecularly, Sharpin, an LFA-1 inhibitor in lymphocyte uropod, was found involved in the LFA-1 deadhesion of lymphocytes; however, both Sharpin and Myosin inhibition had a rather modest impact on adhesiveness. Quantitative 3D immunostaining identified high-affinity LFA-1 and VLA-4 densities at around 50 and 100 molecules/μm2 in basal adherent zones, respectively. Interestingly, a latent adhesiveness of dorsal zones was not grasped by immunostaining but assessed by direct functional assays with beads. The combination of live functional assays, molecular imaging, and genome editing is instrumental to characterizing the spatiotemporal regulation of integrin-mediated adhesiveness at molecular and cell scales, which opens a new perspective to decipher sophisticated phenotypes of motility and guidance.

Assessment of the Functional Activities of Casein Phosphopeptides on Circulating Blood Leukocytes

One of the beneficial effects of peptide-rich protein hydrolysates on diverse pathological conditions has emerged from the concept that their intake as ingredients of dietary supplements or pharmaceutical preparations would have the potential to influence the inflammatory response. Leukocytes are physiologically and strategically positioned in the front line of the defense mechanisms and are the main protagonists of the inflammatory response. Their orchestral extravasation through sequential events that lead them to transmigrate across the endothelial barrier is the hallmark of inflammation. As the direct effects of the milk-derived bioactive molecules on circulating blood leukocyte behavior are still little understood and under explored, we have exposed freshly isolated human blood leukocytes to different caseinate-derived phosphopeptides (CPP) produced by trypsin digestion and studied their influence on cellular adhesiveness and mobilization, two of the most crucial leukocyte functions. We also observed their participation on a wound recovery model. The results herein presented and for the first time reported suggest that the CPP obtained by an enzymatic controlled hydrolysis are potential modulators of leukocyte adhesion by altering the expression of VLA-4 and VLA-5 integrins. CPP can also alter leukocyte trafficking by attracting or repelling them influencing, thus, the inflammatory response. In addition, these peptides might favor the recovery of wounds acting positively on fibroblast migration. Our results support the concept that CPP can add benefits for nutritional deficient patients through the enhancement of some crucial leukocyte functions mitigating the inflammatory components often present in malnutrition states.

Ubiquitin-dependent remodeling of the actin cytoskeleton drives cell fusion.

Cell-cell fusion is a frequent and essential event during development, and its dysregulation causes diseases ranging from infertility to muscle weakness. Fusing cells need to repeatedly remodel their plasma membrane through orchestrated formation and disassembly of actin filaments, but how the dynamic reorganization of the cortical actin cytoskeleton is controlled is still poorly understood. Here, we identified a ubiquitin-dependent toggle switch that establishes reversible actin bundling during mammalian cell fusion. We found that EPS8-IRSp53 complexes stabilize cortical actin bundles at sites of cell contact to promote close membrane alignment. EPS8 monoubiquitylation by CUL3KCTD10 displaces EPS8-IRSp53 from membranes and counteracts actin bundling, a dual activity that restricts actin bundling to allow paired cells to progress with fusion. We conclude that cytoskeletal rearrangements during development are precisely controlled by ubiquitylation, raising the possibility of modulating the efficiency of cell-cell fusion for therapeutic benefit.

Small-molecule antagonist of VLA-4 (GW559090) attenuated neuro-inflammation by targeting Th17 cell trafficking across the blood-retinal barrier in experimental autoimmune uveitis

BackgroundThe integrin VLA-4 (α4β1) plays an important role in leukocyte trafficking. This study investigated the efficacy of a novel topical α4β1 integrin inhibitor (GW559090, GW) in a mouse model for non-infectious posterior uveitis (experimental autoimmune uveitis; EAU) and its effect on intraocular leukocyte subsets.MethodsMice (female; B10.RIII or C57Bl/6; aged 6–8 weeks) were immunized with specific interphotoreceptor retinoid-binding protein (IRBP) peptides to induce EAU. Topically administered GW (3, 10, and 30 mg/ml) were given twice daily either therapeutically once disease was evident, or prophylactically, and compared with vehicle-treated (Veh) and 0.1% dexamethasone-treated (Dex) controls. Mice were sacrificed at peak disease. The retinal T cell subsets were investigated by immunohistochemistry and immunofluorescence staining. The immune cells within the retina, blood, and draining lymph nodes (dLNs) were phenotyped by flow cytometry. The effect of GW559090 on non-adherent, adherent, and migrated CD4+ T cell subsets across a central nervous system (CNS) endothelium was further assayed in vitro and quantitated by flow cytometry.ResultsThere was a significant reduction in clinical and histological scores in GW10- and Dex-treated groups as compared to controls either administered therapeutically or prophylactically. There were fewer CD45+ leukocytes infiltrating the retinae and vitreous fluids in the treated GW10 group (P < 0.05). Immunofluorescence staining and flow cytometry data identified decreased levels of retinal Th17 cells (P ≤ 0.001) in the GW10-treated eyes, leaving systemic T cell subsets unaffected. In addition, fewer Ly6C+ inflammatory monocyte/macrophages (P = 0.002) and dendritic cells (P = 0.017) crossed the BRB following GW10 treatment. In vitro migration assays confirmed that Th17 cells were selectively suppressed by GW559090 in adhering to endothelial monolayers.ConclusionsThis α4β1 integrin inhibitor may exert a modulatory effect in EAU progression by selectively blocking Th17 cell migration across the blood-retinal barrier without affecting systemic CD4+ T cell subsets. Local α4β1 integrin-directed inhibition could be clinically relevant in treating a Th17-dominant form of uveitis.

Inhibition of Tumor-Host Cell Interactions Using Synthetic Heparin Mimetics.

Low-molecular-weight heparin (LMWH) is the guideline-based drug for antithrombotic treatment of cancer patients, while its direct antitumor effects are a matter of ongoing debate. Although therapeutically established for decades, LMWH has several drawbacks mainly associated with its origin from animal sources. Aiming to overcome these limitations, a library of synthetic heparin mimetic polymers consisting of homo- and copolymers of sulfonated and carboxylated noncarbohydrate monomers has recently been synthesized via reversible addition-fragmentation chain transfer polymerization. These heparin mimetics were investigated for their capacities to interfere with simulated steps of tumor cell metastasis. Among them, homo- and copolymers from sodium 4-styrenesulfonate (poly(SSS)) with acrylic acid (poly(SSS-co-AA)) with an MW between 5 and 50 kDa efficiently attenuated cancer cell-induced coagulation and thus platelet activation and degranulation similar to or even better than LMWH. Furthermore, independent of anticoagulant activities, these polymers affected other metastasis-relevant targets with impressive affinities. Hence, they blocked heparanase enzymatic activity outmatching commercial heparins or a glycosidic drug candidate. Furthermore, these polymers bind P-selectin and the integrin VLA-4 similar to or even better than heparin, indicated by a biosensor approach and thus efficiently blocked melanoma cell binding to endothelium under blood flow conditions. This is the first report on the prospects of synthetic heparin mimetics as promising nontoxic compounds in oncology to potentially substitute heparin as an anticoagulant and to better understand its role as an antimetastatic drug.

Integrin-directed antibody-based immunotherapy: focus on VLA-4.

SummaryOne major finding of chronic inflammatory diseases of various origins is the establishment of inflammatory infiltrates, bearing different leukocyte subpopulations, including activated T lymphocytes. Integrins are among the large series of molecular interactions that have been implicated as players in both triggering and maintenance of leukocyte influx from the blood into a given organ parenchyme. Accordingly, blocking the interaction between VLA-6 integrin and laminin, experimentally abrogates heart graft rejection. Many reports have shown that VLA-4 is used by T cells to cross endothelial barriers, as well as to migrate within target tissues. In this respect, a humanized IgG4 anti-VLA-4 monoclonal antibody (specific to the α4-integrin chain of VLA-4) has been successfully applied to treat multiple sclerosis as well as inflammatory bowel disease. Anti-VLA-4 monoclonal antibody has also been applied to block transendothelial passage in other autoimmune diseases, such as rheumatoid arthritis. On this same vein is the action of such a reagent in impairing in vitro transendothial and fibronectin-driven migration of CD4+ and CD8+ T cells expressing high densities of VLA-4 from Duchenne muscular dystrophy patients, thus potentially enlarging the use of this strategy to other diseases. Yet, in a small number of patients, the use of Natalizumab has been correlated with the progressive multifocal leukoencephalopathy, a serious brain infection caused by the John Cunningham virus. This issue restricted the use of the reagent. In this respect, the development of smaller and more specific antibody reagents should be envisioned as a next-generation promising strategy.

Development of Tbet- and CD11c-Expressing B Cells in a Viral Infection Requires T Follicular Helper Cells Outside of Germinal Centers

Tbet+CD11c+ B cells comprise a distinct subset that arises during type 1 pathogen challenge, aging, and autoimmunity in mice and humans. Their developmental reliance upon T cell help and relationship to germinal center (GC) B cells are unclear. We examined Tbet+CD11c+ B cells induced by acute LCMV infections, finding that T follicular helper (Tfh), not T helper 1 (Th1), cells drove their generation prior to GC formation. Genetic fate-tracking and lineage tracing revealed that most Tbet+CD11c+ B cells were not GC-derived and developed independently of cell-intrinsic Bcl6 expression. They localized to the marginal zone where their splenic retention depended upon integrins LFA-1 and VLA-4. After viral clearance, Tbet+CD11c+ B cells formed an uncommon but competitive memory subset, contributing to antibody production and secondary GC seeding upon rechallenge. Therefore, Tbet+CD11c+ B cells are predominantly generated independently of the GC response, yet their development is dependent upon help delivered by Tfh cells.

Functional Cooperation of Cyclin C and c-Myc in Mediating Homotypic Cell Adhesion Via Very Late Antigen-4 Activation and Vascular Cell Adhesion Molecule-1 Induction

AbstractVery late antigen-4 (VLA-4)/vascular cell adhesion molecule-1 (VCAM-1) are a pair of adhesion molecules mediating cell-cell interaction. The binding activity of each depends on its surface expression, yet integrin activity can also be modulated through inside-out signaling. However, the specific intracellular molecules involved in modulating integrin VLA-4 activation via inside-out signaling or in regulating VCAM-1 expression are poorly understood. We show here that constitutive coexpression of cyclin C and c-Myc in hematopoietic BAF-B03 cells induces homotypic cell adhesion, which results from enhanced VLA-4 ligand-binding activity and induced expression of VCAM-1. Furthermore, regulation of cell adhesion appears to be a feature unique to cyclin C, but not other G1 cyclins, E and D3, and its regulatory function is independent of CDK8 kinase activity. Our results provide a novel role for cyclin C and c-Myc in the regulation of cell adhesion through distinct mechanisms.

The Integrin Adaptor Kindlin-3 Is Important for Development and Retention of Marginal Zone B Cells

The Integrin Adaptor Kindlin-3 Is Important for Development and Retention of Marginal Zone B Cells

Natalizumab in Multiple Sclerosis Treatment: From Biological Effects to Immune Monitoring.

Multiple sclerosis is a chronic demyelinating disease of the central nervous system (CNS) with an autoimmune component. Among the recent disease-modifying treatments available, Natalizumab, a monoclonal antibody directed against the alpha chain of the VLA-4 integrin (CD49d), is a potent inhibitor of cell migration toward the tissues including CNS. It potently reduces relapses and active brain lesions in the relapsing remitting form of the disease. However, it has also been associated with a severe infectious complication, the progressive multifocal leukoencephalitis (PML). Using the standard protocol with an injection every 4 weeks it has been shown by a close monitoring of the drug that trough levels soon reach a plateau with an almost saturation of the target cell receptor as well as a down modulation of this receptor. In this review, mechanisms of action involved in therapeutic efficacy as well as in PML risk will be discussed. Furthermore the interest of a biological monitoring that may be helpful to rapidly adapt treatment is presented. Indeed, development of anti-NAT antibodies, although sometimes unapparent, can be detected indirectly by normalization of CD49d expression on circulating mononuclear cells and might require to switch to another drug. On the other hand a stable modulation of CD49d expression might be useful to follow the circulating NAT levels and apply an extended interval dose scheme that could contribute to limiting the risk of PML.

Integrin VLA-4 as a PET imaging biomarker of hyper-adhesion in transgenic sickle mice

AbstractIn sickle cell disease (SCD), very late antigen-4 (VLA-4 or integrin α4β1) mediates the adhesion of reticulocytes to inflamed, proinflammatory endothelium, a key process in promoting vaso-occlusive episodes (VOEs). We hypothesized that a radionuclide tracer targeting VLA-4 could be harnessed as a positron emission tomography (PET) imaging biomarker of VOEs. We tested the VLA-4 peptidomimetic PET tracer 64Cu-CB-TE1A1P-PEG4-LLP2A (64Cu-LLP2A) for imaging hyper-adhesion–associated VOEs in the SCD Townes mouse model. With lipopolysaccharide (LPS)-induced VOEs, 64Cu-LLP2A uptake was increased in the bone marrow of the humeri and femurs, common sites of VOEs in SCD mice compared with non-SCD mice. Treatment with a proven inhibitor of VOEs (the anti-mouse anti-P-selectin monoclonal antibody [mAb] RB40.34) during LPS stimulation led to a reduction in the uptake of 64Cu-LLP2A in the humeri and femurs to baseline levels, implying blockade of VOE hyper-adhesion. Flow cytometry with Cy3-LLP2A demonstrated an increased percentage of VLA-4–positive reticulocytes in SCD vs non-SCD mice in the bone and peripheral blood after treatment with LPS, which was abrogated by anti-P-selectin mAb treatment. These data, for the first time, show in vivo imaging of VLA-4–mediated hyper-adhesion, primarily of SCD reticulocytes, during VOEs. PET imaging with 64Cu-LLP2A may serve as a valuable, noninvasive method for identifying sites of vaso-occlusion and may provide an objective biomarker of disease severity and anti-P-selectin treatment efficacy in patients with SCD.

LFA-1 signals to promote actin polymerization and upstream migration in T cells.

T cell entry into inflamed tissue requires firm adhesion, cell spreading, and migration along and through the endothelial wall. These events require the T cell integrins LFA-1 and VLA-4 and their endothelial ligands ICAM-1 and VCAM-1, respectively. T cells migrate against the direction of shear flow on ICAM-1 and with the direction of shear flow on VCAM-1, suggesting that these two ligands trigger distinct cellular responses. However, the contribution of specific signaling events downstream of LFA-1 and VLA-4 has not been explored. Using primary mouse T cells, we found that engagement of LFA-1, but not VLA-4, induces cell shape changes associated with rapid 2D migration. Moreover, LFA-1 ligation results in activation of the phosphoinositide 3-kinase (PI3K) and ERK pathways, and phosphorylation of multiple kinases and adaptor proteins, whereas VLA-4 ligation triggers only a subset of these signaling events. Importantly, T cells lacking Crk adaptor proteins, key LFA-1 signaling intermediates, or the ubiquitin ligase cCbl (also known as CBL), failed to migrate against the direction of shear flow on ICAM-1. These studies identify novel signaling differences downstream of LFA-1 and VLA-4 that drive T cell migratory behavior.This article has an associated First Person interview with the first author of the paper.

CD49a Regulates Cutaneous Resident Memory CD8+ T Cell Persistence and Response

SUMMARYCD8+ tissue-resident memory T cells (TRM) persist at sites of previous infection, where they provide rapid local protection against pathogen challenge. CD8+ TRM expressing the α1 chain (CD49a) of integrin VLA-1 have been identified within sites of resolved skin infection and in vitiligo lesions. We demonstrate that CD49a is expressed early following T cell activation in vivo, and TGF-β and IL-12 induce CD49a expression by CD8+ T cells in vitro. Despite this rapid expression, CD49a is not required for the generation of a primary CD8+ T cell response to cutaneous herpes simplex virus (HSV) infection, migration of CD8+ T cells across the epidermal basement membrane, or positioning of TRM within basal epidermis. Rather, CD49a supports CD8+ TRM persistence within skin, regulates epidermal CD8+ TRM dendritic extensions, and increases the frequency of IFN-γ+ CD8+ TRM following local antigen challenge. Our results suggest that CD49a promotes optimal cutaneous CD8+ TRM-mediated immunity.

Lymphocytes perform reverse adhesive haptotaxis mediated by LFA-1 integrins.

Cell guidance by anchored molecules, or haptotaxis, is crucial in development, immunology and cancer. Adhesive haptotaxis, or guidance by adhesion molecules, is well established for mesenchymal cells such as fibroblasts, whereas its existence remains unreported for amoeboid cells that require less or no adhesion in order to migrate. We show that, in vitro, amoeboid human T lymphocytes develop adhesive haptotaxis mediated by densities of integrin ligands expressed by high endothelial venules. Moreover, lymphocytes orient towards increasing adhesion with VLA-4 integrins (also known as integrin α4β1), like all mesenchymal cells, but towards decreasing adhesion with LFA-1 integrins (also known as integrin αLβ4), which has not previously been observed. This counterintuitive 'reverse haptotaxis' cannot be explained by existing mechanisms of mesenchymal haptotaxis involving either competitive anchoring of cell edges under tension or differential integrin-activated growth of lamellipodia, because they both favor orientation towards increasing adhesion. The mechanisms and functions of amoeboid adhesive haptotaxis remain unclear; however, multidirectional integrin-mediated haptotaxis might operate around transmigration ports on endothelia, stromal cells in lymph nodes, and inflamed tissue where integrin ligands are spatially modulated.

CD44 engagement enhances acute myeloid leukemia cell adhesion to the bone marrow microenvironment by increasing VLA-4 avidity.

Adhesive properties of leukemia cells shape the degree of organ infiltration and the extent of leukocytosis. CD44 and the integrin VLA-4, a CD49d/CD29 heterodimer, are important factors in progenitor cell adhesion in bone marrow. Here, we report their cooperation in acute myeloid leukemia (AML) by a novel non-classical CD44-mediated way of inside-out VLA-4 activation. In primary AML bone marrow samples from patients and the OCI-AML3 cell line, CD44 engagement by hyaluronan induced inside-out activation of VLA-4 resulting in enhanced leukemia cell adhesion on VCAM-1. This was independent of VLA-4 affinity regulation but based on ligand-induced integrin clustering on the cell surface. CD44-induced VLA-4 activation could be inhibited by the Src family kinase inhibitor PP2 and the multikinase inhibitor midostaurin. As a further consequence, the increased adhesion on VCAM-1 allowed AML cells to bind stromal cells strongly. Thereby, the VLA-4/VCAM-1 interaction promoted activation of Akt, MAPK, NF-kB and mTOR signaling and decreased AML cell apoptosis. Collectively, our investigations provide a mechanistic description of an unusual CD44 function in regulating VLA-4 avidity in AML, enhancing AML cell retention in the supportive bone marrow microenvironment.

Cluster of differentiation 44 promotes osteosarcoma progression in mice lacking the tumor suppressor Merlin.

Merlin is a versatile tumor suppressor protein encoded by the NF2 gene. Several lines of evidence suggest that Merlin exerts its tumor suppressor activity, at least in part, by forming an inhibitory complex with cluster of differentiation 44 (CD44). Consistently, numerous NF2 mutations in cancer patients are predicted to perturb the interaction of Merlin with CD44. We hypothesized that disruption of the Merlin-CD44 complex through loss of Merlin, unleashes putative tumor- or metastasis-promoting functions of CD44. To evaluate the relevance of the Merlin-CD44 interaction in vivo, we compared tumor growth and progression in Cd44-positive and Cd44-negative Nf2-mutant mice. Heterozygous Nf2-mutant mice were prone to developing highly metastatic osteosarcomas. Importantly, while the absence of the Cd44 gene had no effect on the frequency of primary osteosarcoma development, it strongly diminished osteosarcoma metastasis formation in the Nf2-mutant mice. In vitro assays identified transendothelial migration as the most prominent cellular phenotype dependent on CD44. Adhesion to endothelial cells was blocked by interfering with integrin α4β1 (very late antigen-4, VLA-4) on osteosarcoma cells and CD44 upregulated levels of integrin VLA-4 β1 subunit. Among other putative functions of CD44, which may contribute to the metastatic behavior, the passage through the endothelial cells also appears to be critical in vivo, as CD44 significantly promoted formation of lung metastasis upon intravenous injection of osteosarcoma cells into immunocompromised mice. Altogether, our results strongly suggest that CD44 plays a metastasis-promoting role in the absence of Merlin.

Integrin-Mediated Adhesion and Chemoresistance of Acute Lymphoblastic Leukemia Cells Residing in the Bone Marrow or the Central Nervous System.

Acute Lymphoblastic Leukemia (ALL) is the most common cancer in childhood. Despite a significantly improved prognosis over the last decade with a 5-years survival rate of ~90%, treatment-related morbidity remains substantial and relapse occurs in 10–15% of patients (1). The most common site of relapse is the bone marrow, but early colonization and subsequent reoccurrence of the disease in the central nervous system (CNS) also occurs. Integrins are a family of cell surface molecules with a longstanding history in cancer cell adherence, migration and metastasis. In chronic lymphoblastic leukemia (CLL), the VLA-4 integrin has been acknowledged as a prognostic marker and mounting evidence indicates that this and other integrins may also play a role in acute leukemia, including ALL. Importantly, integrins engage in anti-apoptotic signaling when binding extracellular molecules that are enriched in the bone marrow and CNS microenvironments. Here, we review the current evidence for a role of integrins in the adherence of ALL cells within the bone marrow and their colonization of the CNS, with particular emphasis on mechanisms adding to cancer cell survival and chemoresistance.

CD49a mediates cutaneous resident memory CD8+ T cell persistence and response

Abstract Resident memory CD8+ T cells (TRM) persist at sites of previous infection where they provide rapid local protection against pathogen challenge. CD8+ TRM expressing the a1 chain (CD49a) of integrin VLA-1 have been identified within sites of resolved skin infection as well as in vitiligo lesions. This study examines the signals that regulate CD8+ T cell CD49a expression and its requirement for cutaneous TRM formation and response. We demonstrate that CD49a was expressed early following T cell activation in vivo, and that TGF-b as well as IL-12 induced CD49a expression by CD8+ T cells in vitro. Despite this rapid expression, CD49a was not required for the generation of a primary CD8+ T cell response to cutaneous herpes simplex virus (HSV) infection. Rather, CD49a mediated epidermal CD8+ TRM interaction with the extracellular matrix, supported CD8+ TRM persistence within the skin, and increased the frequency of CD8+ TRM that secrete IFN-g following local antigen challenge. Thus, our results suggest CD49a promotes optimal cutaneous CD8+ TRM-mediated immunity.