Stimulator of interferon genes (STING) is a protein that mediates the production of type I interferons in response to the cytosolic DNA. It can also influence the expression of major histocompatibility complex class I (MHC-I) molecules. STING agonists may therefore be used in cancer immunotherapy to enhance anti-tumor immunity. However, in tumors associated with human papillomaviruses (HPV), STING signaling can be inhibited by the viral E2, E5, E6, and E7 proteins. The aim of this project is to study the activation of the STING signaling pathway in mouse and human tumor cell lines producing HPV proteins and to evaluate the inhibitory effect of these proteins on the activation of STING-mediated immune responses. As a possible enhancement of STING activation, inhibition of aspartate b-hydroxylase will be tested because it may reduce the inhibitory effect of the E7 oncoprotein. An anti-tumor effect of combination immunotherapy, including DNA immunization against the E7 oncoprotein using a gene gun, will be tested in mouse tumor models characterized by different levels of MHC-I expression and different modes of MHC-I downregulation. Tumor microenvironment will be analyzed to elucidate mechanisms involved in immunotherapy. The results obtained may help to improve immunotherapy of HPV-driven tumors with reduced MHC-I expression.
Five relevant publications of the research group:
Piatakova A, Polakova I, Smahelova J, Johari SD, Nunvar J, Smahel M. Distinct responsiveness of tumor-associated macrophages to immunotherapy of tumors with different mechanisms of major histocompatibility complex class I downregulation. Cancers 2021; 13: 3057.
Lhotakova K, Grzelak A, Polakova I, Vackova J, Smahel M. Establishment and characterization of a mouse tumor cell line with irreversible downregulation of MHC class I molecules. Oncol Rep. 2019; 42: 2826-2835.
Grzelak A, Polakova I, Smahelova J, Vackova J, Pekarcikova L, Tachezy R and Smahel M: Experimental combined immunotherapy of tumours with major histocompatibility complex class I downregulation. Int J Mol Sci 2018; 19: 3693
Smahel M, Polakova I, Duskova M, Ludvikova V, Kastankova I. The effect of helper epitopes and cellular localization of an antigen on the outcome of gene gun DNA immunization. Gene Ther 2014; 21: 225-32.
Smahel M, Sima P, Ludvikova V, Marinov I, Pokorna D, Vonka V. Immunisation with modified HPV16 E7 genes against mouse oncogenic TC-1 cell sublines with downregulated expression of MHC class I molecules. Vaccine 2003; 21: 1125-36.Apply to the project