Swainsonine, an alpha-mannosidase inhibitor, may worsen cervical cancer progression through the increase in myeloid derived suppressor cells population

Abstract

Cervical cancer, caused by high oncogenic risk Human Papillomavirus (HPV) infection, continues to be a public health problem, mainly in developing countries. Using peptide phage display as a tool to identify potential molecular targets in HPV associated tumors, we identified α-mannosidase, among other enriched sequences. This enzyme is expressed in both tumor and inflammatory compartment of the tumor microenvironment. Several studies in experimental models have shown that its inhibition by swainsonine (SW) led to inhibition of tumor growth and metastasis directly and indirectly, through activation of macrophages and NK cells, promoting anti-tumor activity. Therefore, the aim of this work was to test if swainsonine treatment could modulate anti-tumor immune responses and therefore interfere in HPV associated tumor growth. Validation of our biopanning results showed that cervical tumors, both tumor cells and leukocytes, expressed α-mannosidase. Ex vivo experiments with tumor associated macrophages showed that SW could partially modulate macrophage phenotype, decreasing CCL2 secretion and impairing IL-10 and IL-6 upregulation, which prompted us to proceed to in vivo tests. However, in vivo , SW treatment increased tumor growth. Investigation of the mechanisms leading to this result showed that SW treatment significantly induced the accumulation of myeloid derived suppressor cells in the spleen of tumor bearing mice, which inhibited T cell activation. Our results suggested that SW contributes to cervical cancer progression by favoring proliferation and accumulation of myeloid cells in the spleen, thus exacerbating these tumors systemic effects on the immune system, therefore facilitating tumor growth.

Biologically active indolizidine alkaloids

“…Subsequent studies explored the in vivo effects of SW on melanoma, 29 Ehrlich ascites carcinoma, 30 colorectal cancer, 31 human liver cancer, 32 lymphoma, 33 and leukemia 34 ; the results showed that all patients obtained good therapeutic effects 30,32,34,35 . The specific mechanisms of action include the following effects (Figure 3): inhibition of α‐mannosidase II, 137,138 promotion of tumor cell apoptosis, 139 enhancement of the immune system, 140 increase of intracellular calcium ion concentration, inactivation of the PI3K/AKT/mTOR signaling pathway, and repression of miR‐92a 141 . As a novel anticancer drug candidate, the biosynthesis of SW has also received attention as recently reviewed 142 …”

The Formation and Therapeutic Update of Tumor-Associated Macrophages in Cervical Cancer

“…Scientists found that CD68+ TAMs in cervical tumor presented a mixed CXCL10 (M1)/CD163+ (M2) pattern [35]. CD45+ and CD105+ are also unspecific for certain subtypes [81,87,88]. Increasing studies have focused on which subtype of macrophages the TAMs belongs to.…”

Autocoleta cervicovaginal no rastreamento do câncer do colo do útero: aceitabilidade, detecção de Papilomavírus Humano de alto risco oncogênico e pesquisa de biomarcadores

“…A atividade da α-manosidase no câncer pode ter seu efeito nas células tumorais, por meio da migração e invasão através de glicoproteínas, bem como por meio das células do microambiente tumoral. Utilizando-se um inibidor farmacológico da α-manosidase, observou-se aumento de células mielóides supressoras136 . Estas células demonstraram ser responsáveis pela supressão de resposta de células T anti-tumorais.…”

“…A taxa de CST IV (e de certo modo CST III, com predominância de L. iners) não era diferente em mulheres HPV negativas ou HPV positivas/LSIL, mas substancialmente maior para mulheres com HSIL, sugerindo que a presença de microbioma depletado de diversidade de Lactobacillus pode estar mais Com a necessidade de desenvolver novas estratégias para detecção de lesões precursoras ou mesmo neoplásicas, estudou-se outra proteína, a α-manosidase.Utilizando o método de apresentação de fagos peptídeos (phage display), identificou-se sequências peptídicas com afinidade preferencial para linhagens celulares e tumores do colo do útero. Uma das sequências correspondeu à α-manosidase237 . Observou-se que os tecidos cervicais expressavam esta proteína, e que a expressão era maior em lesões de alto grau e câncer, em comparação com a mucosa normal.…”

“…Em nossa série não houve diferença em relação à expressão de α-manosidase nos grupos PS e AC, nas participantes NLP; nos estratos NIC 1 e NIC 2+ observou-se aumento, com significância estatística, entre as participantes NLP e NIC 2+, apenas no grupo AC. No entanto, observou-se, como no descrito por Lepique e colaboradores anteriormente, correlação positiva com a gravidade da lesão237 .…”