Systemic Administration of Platelets Incorporating Inactivated Sendai Virus Eradicates Melanoma in Mice

Abstract

Tumor microenvironments include a number of fibrin clots due to the microbleeding caused by cancer cell invasion into blood vessels, which suggests the potential utility of a platelet vector for systemic cancer treatment. We previously reported that inactivated Sendai virus (hemagglutinating virus of Japan; HVJ) envelope (HVJ-E) activates anti-tumor immunity and induces cancer cell-selective apoptosis. The hemagglutination activity that blocks the systemic administration of HVJ-E was dramatically attenuated by incorporation into platelets. Platelets incorporating HVJ-E (PH complex) were then injected into the tail veins of B16F10 melanoma-bearing mice. The PH complex primarily accumulated in tumor tissues and caused the significant accumulation of various immune cells in the tumor bed. Injections of the PH complex to the melanoma-bearing mouse significantly reduced the tumor size, and the tumor growth was ultimately arrested. Secretion of the chemokine regulated upon activation normal T-expressed and presumably secreted (RANTES) was upregulated following PH stimulation. The RANTES-depletion in melanoma-bearing mice significantly attenuated the cytotoxic T lymphocyte activity and led to a dramatic abrogation of the mouse melanoma suppression induced by the PH complex. Thus, a platelet vector incorporating viral particles, a Trojan horse for cancer treatment, will provide a new approach for cancer therapy using oncolytic viruses.

Cytoplasmic calcium increase via fusion with inactivated Sendai virus induces apoptosis in human multiple myeloma cells by downregulation of c-Myc oncogene

“…We showed that HVJ-E exhibited cytotoxicity against various MM cells but not healthy PBMCs. Human umbilical vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs) were also treated with HVJ-E, and the proliferation of HUVECs and HAECs was not inhibited (Supplementary Figure 1F–1G), which is consistent with our previous report [31]. …”

Virus-stimulated neutrophils in the tumor microenvironment enhance T cell-mediated anti-tumor immunity

“…Direct intratumoral injection of HVJ-E activates anti-tumor immunity and induces direct cancer killing [25–27]. HVJ-E target cells in the TME include cancer cells, macrophages, dendritic cells, fibroblasts and endothelial cells [25–28]. As a result, HVJ-E can act as a modulator of the TME for cancer therapy.…”

Oncolytic Sendai virus‐induced tumor‐specific immunoresponses suppress “simulated metastasis” of squamous cell carcinoma in an immunocompetent mouse model

“…For activation of CTLs, direct presentation of tumor‐associated antigens to CD8 + lymphocytes by DCs is essential in a mouse glioma model using oncolytic adenovirus . Nishikawa et al reported that systemic administration of platelets incorporating inactivated Sendai virus induced the accumulation of CD4 + /CD8 + lymphocytes in mouse melanomas . In their experiments, when CD4 + or CD8 + lymphocytes were depleted, tumor suppression was significantly abrogated, especially in CD8 + lymphocyte‐depleted group.…”