Dataset Information

CD47 Blockade and Cowpea Mosaic Virus Nanoparticle In Situ Vaccination Triggers Phagocytosis and Tumor Killing.

ABSTRACT: Contemporary immunotherapies, e.g., those that target the CTLA-4 and PD-1/PD-L1 axis, act on T cells to reinstate their antitumor activity. An alternative, and possibly more powerful approach is to target and reprogram the innate immune system within the tumor microenvironment. To this end, blockade of CD47 has been demonstrated as an attractive approach. Blockade of CD47 inhibits antiphagocytic signals therefore inducing macrophage phagocytosis of cancer cells. CD47 blockade also primes antitumor T-cell responses by either activating antigen-presenting cells or inhibiting interactions between CD47 on cancer cells and the matricellular protein thrombospondin-1 on T cells. Here, a combination immunotherapy is identified using cowpea mosaic virus (CPMV) in situ vaccination and CD47-blocking antibodies. The CPMV in situ vaccine synergizes with CD47 blockade, because CPMV in situ vaccination activates the innate immune system, leading to recruitment and activation of phagocytes. Therefore, the combination therapy targets monocytes and boosts their ability of cancer cell phagocytosis, in turn priming the adaptive immune system leading to a potent antitumor immune response. This work presents a novel strategy to promote macrophage activity to kill tumor cells, and hold promise to enhance T cells targeted immunotherapies by inducing both innate and adaptive arms of immune system.

SUBMITTER: Wang C

PROVIDER: S-EPMC6633909 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

CD47 Blockade and Cowpea Mosaic Virus Nanoparticle In Situ Vaccination Triggers Phagocytosis and Tumor Killing.

Wang Chao C Steinmetz Nicole F NF

Advanced healthcare materials 20190306 8

Contemporary immunotherapies, e.g., those that target the CTLA-4 and PD-1/PD-L1 axis, act on T cells to reinstate their antitumor activity. An alternative, and possibly more powerful approach is to target and reprogram the innate immune system within the tumor microenvironment. To this end, blockade of CD47 has been demonstrated as an attractive approach. Blockade of CD47 inhibits antiphagocytic signals therefore inducing macrophage phagocytosis of cancer cells. CD47 blockade also primes antitum ...[more]

PMID: 30838815

Similar Datasets

Project description:Cancer immunotherapy approaches have emerged as novel treatment regimens against cancer. A particularly interesting avenue is the concept of in situ vaccination, where immunostimulatory agents are introduced into an identified tumor to overcome local immunosuppression and, if successful, mount systemic antitumor immunity. We had previously shown that nanoparticles from cowpea mosaic virus (CPMV) are highly potent in inducing long-lasting antitumor immunity when used as an in situ vaccine in various tumor mouse models. Here we asked whether the nanoparticles from tobacco mosaic virus (TMV) could also be applied as an in situ vaccine and, if so, whether efficacy or mechanism of immune-activation would be affected by the nanoparticle size (300 × 18 nm native TMV vs 50 × 18 nm short TMV nanorods), shape (nanorods vs spherical TMV, termed SNP), or state of assembly (assembled TMV rod vs free coat protein, CP). Our studies indicate that CPMV, but less so TMV, elicits potent antitumor immunity after intratumoral treatment of dermal melanoma (B16F10 using C57BL/6 mice). TMV and TMVshort slowed tumor growth and increased survival time, however, at significantly lower potency compared to that of CPMV. There were no apparent differences between TMV, TMVshort, or the SNP indicating that the aspect ratio does not necessarily play a role in plant viral in situ vaccines. The free CPs did not elicit an antitumor response or immunostimulation, which may indicate that a multivalent assembly is required to trigger an innate immune recognition and activation. Differential potency of CPMV vs TMV can be explained with differences in immune-activation: data indicate that CPMV stimulates an antitumor response through recruitment of monocytes into the tumor microenvironment (TME), establishing signaling through the IFN-? pathway, which also leads to recruitment of tumor-infiltrated neutrophils (TINs) and natural killer (NK) cells. Furthermore, the priming of the innate immune system also mounts an adaptive response with CD4+ and CD8+ T cell recruitment and establishment of effector memory cells. While the TMV treatment also lead to the recruitment of innate immune cells as well as T cells (although to a lesser degree), key differences were noted in cyto/chemokine profiling with TMV inducing a potent immune response early on characterized by strong pro-inflammatory cytokines, primarily IL-6. Together, data indicate that some plant viral nanotechnology platforms are more suitable for application as in situ vaccines than others; understanding the intricate differences and underlying mechanism of immune-activation may set the stage for clinical development of these technologies.

Project description:Cowpea mosaic virus (CPMV) is a nucleoprotein nanoparticle that functions as a highly potent immunomodulator when administered intratumorally and is used as an in situ vaccine. CPMV in situ vaccination remodels the tumor microenvironment and primes a highly potent, systemic, and durable antitumor immune response against the treated and untreated, distant metastatic sites (abscopal effect). Potent efficacy was demonstrated in multiple tumor mouse models and, most importantly, in canine cancer patients with spontaneous tumors. Data indicate that presence of anti-CPMV antibodies are not neutralizing and that in fact opsonization leads to enhanced efficacy. Plant viruses are part of the food chain, but to date, there is no information on human exposure to CPMV. Therefore, patient sera were tested for the presence of immunoglobulins against CPMV, and indeed, >50% of deidentified patient samples tested positive for CPMV antibodies. To get a broader sense of plant virus exposure and immunogenicity in humans, we also tested sera for antibodies against tobacco mosaic virus (>90% patients tested positive), potato virus X (<20% patients tested positive), and cowpea chlorotic mottle virus (no antibodies were detected). Further, patient sera were analyzed for the presence of antibodies against the coliphage Qβ, a platform technology currently undergoing clinical trials for in situ vaccination; we found that 60% of patients present with anti-Qβ antibodies. Thus, data indicate human exposure to CPMV and other plant viruses and phages. Next, we thought to address agronomical safety; i.e., we examined the fate of CPMV after intratumoral treatment and oral gavage (to mimic consumption by food). Because live CPMV is used, an important question is whether there is any evidence of shedding of infectious particles from mice or patients. CPMV is noninfectious toward mammals; however, it is infectious toward plants including black-eyed peas and other legumes. Biodistribution data in tumor-bearing and healthy mice indicate little leaching from tumors and clearance via the reticuloendothelial system followed by biliary excretion. While there was evidence of shedding of RNA in stool, there was no evidence of infectious particles when plants were challenged with stool extracts, thus indicating agronomical safety. Together these data aid the translational development of CPMV as a drug candidate for cancer immunotherapy.

Dataset Information

CD47 Blockade and Cowpea Mosaic Virus Nanoparticle In Situ Vaccination Triggers Phagocytosis and Tumor Killing.

Publications

CD47 Blockade and Cowpea Mosaic Virus Nanoparticle In Situ Vaccination Triggers Phagocytosis and Tumor Killing.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets