Tumor heterogeneity is one of the major obstacles to successful cancer treatment. While heterogeneity of tumor cells has been intensively studied, heterogeneity of other parameters of tumor microenvironment is less understood. In this project, heterogeneity within both tumor and immune cell compartments will be analyzed with respect to cancer immunotherapy. In early human tumors, intratumoral heterogeneity of MHC class I phenotype is usually observed and may serve as a predictor of tumor progression and a response to immunotherapy. Downregulation of MHC-I molecules is one of the most frequent mechanisms of the tumor escape from host immunity. Overcoming this escape mechanism by cancer immunotherapy will be studied in a mouse tumor model by using TC-1 clones with both reversibly and irreversibly reduced MHC-I expression. These cell lines will be inoculated subcutaneously either separately or in a mix mimicking MHC-I heterogeneity in tumors. Tumor microenvironment will be analyzed by flow cytometry, immunohistochemistry, and RNA sequencing to evaluate positional and temporal tumor heterogeneity and possible mechanisms contributing to tumor escape. Combined cancer immunotherapy will induce both adaptive immunity (by DNA vaccination via a gene gun) and innate immunity (by stimulation of macrophages and/or NK cells) and inhibit intratumoral immunosuppression (by monoclonal antibodies).
Five relevant publications of the research group:
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. PD-1/PD-L1 Blockade Therapy for Tumors with Downregulated MHC Class I Expression. Int J Mol Sci. 2017; 18: 1331.
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