Modulation of stress and immune response by Amblyomin-X results in tumor cell death in a horse melanoma model

Abstract

We have investigated Amblyomin-X-treated horse melanomas to better understand its mode of action through transcriptome analysis and the in vivo model. Amblyomin-X is a Kunitz-type homologous protein that selectively leads to the death of tumor cells via ER stress and apoptosis, currently under investigation as a new drug candidate for cancer treatment. Melanomas are immunogenic tumors, and a better understanding of the immune responses is warranted. Equine melanomas are spontaneous and not so aggressive as human melanomas are, as this study shows that the in vivo treatment of encapsulated horse melanoma tumors led to a significant reduction in the tumor size or even the complete disappearance of the tumor mass through intratumoral injections of Amblyomin-X. Transcriptome analysis identified ER-and mitochondria-stress, modulation of the innate immune system, apoptosis, and possibly immunogenic cell death activation. Interactome analysis showed that Amblyomin-X potentially interacts with key elements found in transcriptomics. Taken together, Amblyomin-X modulated the tumor immune microenvironment in different ways, at least contributing to induce tumor cell death. Melanoma is a type of cancer arising from the malignant transformation of melanocytes, pigment producing-cells found predominantly in the basal layer of the epidermis and eyes. Cutaneous melanoma is the most aggressive and treatment-resistant form of skin cancer responsible for the vast majority of skin cancer-related deaths in the Caucasian population 1. The global incidence of melanoma continues to increase at an alarming rate, despite decades of public prevention programs in many countries. Around 232,000 new cases of skin cancer were recorded worldwide in 2012, accounting for 1.6% of all new cases of cancer back then, while over 300,000 new cases of melanoma were diagnosed worldwide in 2018, according to the World Cancer Research Foundation 2,3. In Brazil, 1,547 deaths were recorded in 2013 due to melanoma, with around 5,690 new cases reported back then, while around 6,260 new cases were expected due in 2018, according to the National Cancer Institute (INCA) 4. Cutaneous melanoma usually affects a higher proportion of patients, in the age range 40-60 years. They can be treated by surgical excision when detected in the early stage (0, I, II and resectable III), however, in the later stages (unresectable III, IV and recurrent melanoma) the treatment options are chemotherapy, target therapy (BRAF/ MEK pathway inhibitors), immunotherapy (checkpoint blockade CTLA-4 receptor inhibition, PD-1 ↔ PD-L1 axis inhibition, and interferon-gamma immunotherapy), or a combination of them. Death in most patients is caused by metastatic disease which may have evolved from the primary tumor. Therefore, there is a need for new

Insights into the Role of Tick Salivary Protease Inhibitors during Ectoparasite–Host Crosstalk

“…Moreover, Amblyomin-X modulates Rho-GTPases and uPAR signaling and reduces the release of MMPs, thereby disrupting the actin cytoskeleton and decreasing the cellular migration of tumor cell lines [ 141 ]. In a pre-clinical study, Amblyomin-X was administered to mice harboring orthotopic kidney tumors and significantly decreased lung metastasis [ 144 ]. Impressively, the injected dose of Amblyomin-X was safe, with any symptoms of toxicity being reversible and only seen at higher doses.…”

“…Impressively, the injected dose of Amblyomin-X was safe, with any symptoms of toxicity being reversible and only seen at higher doses. In a horse melanoma model, Amblyomin-X modulated the tumor immune microenvironment by inducing tumor cell death and significantly reducing the tumor size [ 144 ].…”

The tick and I: Parasite‐host interactions between ticks and humans

“…In one example, the anti-angiogenic effect of some salivary components may be of interest for cancer therapy. The Kunitz-type serine protease inhibitor Amblyomin-X from Amblyomma cajennense reduces tumor growth and metastasis [152][153][154][155][156][157][158]. Amblyomin X also inhibits FXa as well as VEGF-Ainduced angiogenesis and endothelial PECAM-1 (CD31) expression [159].…”

Die Zecke und ich: Parasiten‐Wirt‐Interaktionen zwischen Zecken und Menschen

“…So kann die antiangiogene Wirkung einiger Speichelkomponenten für die Krebstherapie interessant sein. Der Kunitz-Typ-Serinproteaseinhibitor Amblyomin-X aus Amblyomma cajennense verringert Tumorwachstum und Metastasierung [152][153][154][155][156][157][158]. Amblyomin X hemmt auch FXa sowie VEGF-A-induzierte Angiogenese und endotheliale PECAM-1 (CD31)-Expression [159].…”