Efekti sistemske aplikacije IL-33 na progresiju mišjeg melanoma

Abstract

Melanom je jedan od najagresivnijih tumora koji karakterišu povećan invazivni i metastatski potencijal, kao i sticanje rezistencije na terapeutike. IL-33 je član familije IL-1 koji reguliše urođeni i stečeni imunski odgovor. Uloga IL-33 u tumoru je kompleksna i nije u potpunosti razjašnjena. Cilj studije je da se ispitaju efekti sistemske aplikacije IL-33 na progresiju mišjeg melanoma, kao i na modulaciju antitumorskog imunskog odgovora. Miševima čistog soja C57BL/6 je subkutanom aplikacijom ćelija B16-F1 i B16-F10 varijeteta mišjeg melanoma transplantiran primarni melanom, dok su im eksperimentalne metastaze indukovane posle intravenske aplikacije ćelija. Nakon različitih modaliteta aplikacije mišjeg rekombinantnog IL-33, ispitivan je efekat IL-33 na rast i metastaziranje melanoma. Analiziran je uticaj IL-33 na modulaciju imunskog odgovora u metastaskom tkivu pluća. IL-33 suprimira rast primarnog melanoma i sa većim (B16-F10) i sa manjim metastatskim potencijalom (B16-F1), dok s druge strane stimuliše hematogeno metastaziranje B16-F1 varijeteta melanoma u pluća. Prometastatska aktivnost IL-33 se ogleda u tome što redukuje citotoksički kapacitet i favorizuje imunosupresivni fenotip CD8+ T limfocita u metastatskom tkivu pluća. Zabeležena je povećana akumulacija mijeloidnih supresorskih ćelija, kao i regulatornih T limfocita. Prometastatski efekat IL-33 dodatno je potvrđen i nalazom povećane koncentracije IL-33 u serumu obolelih od melanoma sa detektovanim regionalnim metastazama. Dobijeni nalaz ukazuje da uprkos supresivnom delovanju na rast primarnog melanoma, IL-33 podstiče rast hematogenih metastaza i to tako što smanjuje efikasnost stečenog antitumorskog imunskog odgovora. Prometastatski efekat IL-33 u mišjem melanomu dovodi u pitanje njegovu eventualnu terapijsku primenu.

Melanoma is one of the most aggressive tumors, characterized by high invasiveness, metastatic potential and resistance to therapeutics. IL-33 is member of IL-1 cytokine family that regulates both innate and acquired immune response. The role of IL-33 in tumor progression is complex and not fully understood. The aim of the study is to evaluate effects of systemic IL-33 application on murine melanoma progression, as well as the effects of IL-33 on modulation of antitumor immune response. For the assessment of tumor growth, wild-type C57BL/6 mice were injected subcutaneously with B16-F1 or B16-F10 cells, whilst for experimental metastasis assays, malignant cells were injected intravenously. Using different modalities of IL-33 application, effects of the mouse recombinant IL-33 on growth and melanoma metastasis were evaluated. Effects of IL-33 on antitumor immune response in metastatic lungs were analyzed. IL-33 restricted primary tumor growth of both high metastatic (B16-F10) and low metastatic (B16-F1) variant, while on the opposite promoted growth of the B16-F1 melanoma metastasis in the lungs. Prometastatic IL-33 activity is reflected in significant reduction of CD8+ T cells cytotoxicity and promotion of CD8+ T cell immunosuppressive phenotype. There was a significant accumulation of myeloid suppressor cells and regulatory T cells in the metastatic lung. The significance of IL-33 for melanoma metastases was also documented in a significantly increased level of serum IL-33 melanoma patients with regional metastases. These findings implicate that, despite restrictive effects on primary melanoma, IL-33 promotes growth of hematogenous melanoma metastasis in mice by modulation of acquired immune response, thus questioning its usage in therapy of human advanced melanoma.