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Plexin-A4 Mediates Cytotoxic T-cell Trafficking and Exclusion in Cancer.

ABSTRACT: Cytotoxic T cell (CTL) infiltration of the tumor carries the potential to limit cancer progression, but their exclusion by the immunosuppressive tumor microenvironment hampers the efficiency of immunotherapy. Here, we show that expression of the axon guidance molecule Plexin-A4 (Plxna4) in CTLs, especially in effector/memory CD8⁺ T cells, is induced upon T-cell activation, sustained in the circulation, but reduced when entering the tumor bed. Therefore, we deleted Plxna4 and observed that Plxna4-deficient CTLs acquired improved homing capacity to the lymph nodes and to the tumor, as well as increased proliferation, both achieved through enhanced Rac1 activation. Mice with stromal or hematopoietic Plxna4 deletion exhibited enhanced CTL infiltration and impaired tumor growth. In a melanoma model, adoptive transfer of CTLs lacking Plxna4 prolonged survival and improved therapeutic outcome, which was even stronger when combined with anti-programmed cell death protein 1 (PD-1) treatment. PLXNA4 abundance in circulating CTLs was augmented in melanoma patients versus healthy volunteers but decreased after the first cycle of anti-PD-1, alone or in combination with anti-cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4), in those patients showing complete or partial response to the treatment. Altogether, our data suggest that Plxna4 acts as a "checkpoint," negatively regulating CTL migration and proliferation through cell-autonomous mechanisms independent of the interaction with host-derived Plxna4 ligands, semaphorins. These findings pave the way toward Plxna4-centric immunotherapies and propose Plxna4 detection in circulating CTLs as a potential way to monitor the response to immune checkpoint blockade in patients with metastatic melanoma.

SUBMITTER: Celus W

PROVIDER: S-EPMC7612191 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Νon-small cell lung cancer (NSCLC) is the most frequently diagnosed type of cancer, and the most prevalent cause of cancer-associated mortality. The present study aimed to investigate whether microRNA (miR)-564 influences NSCLC progression by regulating NSCLC cell growth and migration, via targeting plexin A4. Therefore, the expression levels of miR-564 and plexin A4 were evaluated in NSCLC specimens or cells using reverse transcription-quantitative PCR. Furthermore, colony formation and Cell Counting Kit-8 assays were performed to determine the proliferative ability of NSCLC cells. The cell migration capacity was assessed using a Transwell assay. In addition, to examine the binding ability of miR-564 on the plexin A4 3'-untranslated region (3'UTR), a dual-luciferase reporter assay was performed. A mouse xenograft model was established to evaluate the effect of miR-564 knockdown on tumor growth in vivo, whereas the expression of plexin A4 and Ki67 in NSCLC tissues was detected using immunohistochemistry. Notably, miR-564 was downregulated in both NSCLC cell lines and tissues, while its overexpression, following transfection with miR-564 mimics, attenuated the proliferation and proliferation, migration and invasion of NSCLC cells. By contrast, silencing of miR-564 using a miR-564 inhibitor promoted NSCLC cell proliferation, migration and invasion. The luciferase assay revealed that miR-564 directly targeted the plexin A4 3'UTR in A549 and H460 cells. Additionally, the overexpression of plexin A4 rescued the effect of miR-564 on NSCLC cell proliferation, migration and invasion abilities. Further in vivo studies demonstrated that miR-564 knockdown promoted NSCLC growth, while miR-564 overexpression resulted in the opposite effect in nude mice. Overall, the results of the present study revealed that miR-564 promotes the proliferation and migration of NSCLC cells, both in vitro and in vivo, via targeting plexin A4. Therefore, miR-564 may be considered as a possible therapeutic target for NSCLC.

Project description:Diverse neuronal populations with distinct cellular morphologies coordinate the complex function of the nervous system. Establishment of distinct neuronal morphologies critically depends on signaling pathways that control axonal and dendritic development. The Sema3A-Nrp1/PlxnA4 signaling pathway promotes cortical neuron basal dendrite arborization but also repels axons. However, the downstream signaling components underlying these disparate functions of Sema3A signaling are unclear. Using the novel PlxnA4KRK-AAA knock-in male and female mice, generated by CRISPR/cas9, we show here that the KRK motif in the PlxnA4 cytoplasmic domain is required for Sema3A-mediated cortical neuron dendritic elaboration but is dispensable for inhibitory axon guidance. The RhoGEF FARP2, which binds to the KRK motif, shows identical functional specificity as the KRK motif in the PlxnA4 receptor. We find that Sema3A activates the small GTPase Rac1, and that Rac1 activity is required for dendrite elaboration but not axon growth cone collapse. This work identifies a novel Sema3A-Nrp1/PlxnA4/FARP2/Rac1 signaling pathway that specifically controls dendritic morphogenesis but is dispensable for repulsive guidance events. Overall, our results demonstrate that the divergent signaling output from multifunctional receptor complexes critically depends on distinct signaling motifs, highlighting the modular nature of guidance cue receptors and its potential to regulate diverse cellular responses.SIGNIFICANCE STATEMENT The proper formation of axonal and dendritic morphologies is crucial for the precise wiring of the nervous system that ultimately leads to the generation of complex functions in an organism. The Semaphorin3A-Neuropilin1/Plexin-A4 signaling pathway has been shown to have multiple key roles in neurodevelopment, from axon repulsion to dendrite elaboration. This study demonstrates that three specific amino acids, the KRK motif within the Plexin-A4 receptor cytoplasmic domain, are required to coordinate the downstream signaling molecules to promote Sema3A-mediated cortical neuron dendritic elaboration, but not inhibitory axon guidance. Our results unravel a novel Semaphorin3A-Plexin-A4 downstream signaling pathway and shed light on how the disparate functions of axon guidance and dendritic morphogenesis are accomplished by the same extracellular ligand in vivo.

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Plexin-A4 Mediates Cytotoxic T-cell Trafficking and Exclusion in Cancer.

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