Experimental Combined Immunotherapy of Tumours with Major Histocompatibility Complex Class I Downregulation

International Journal of Molecular Sciences

Ruth Tachezy¹  Ingrid Polakova¹  Julie Vackova¹  Jana Smahelova¹  Adrianna Grzelak¹  Michal Smahel¹  Lucie Pekarcikova¹ 

[1] Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, 25250 Vestec, Czech Republic;

关键词: MHC-I;    cancer immunotherapy;    DNA immunization;    CpG ODN;    α-galactosylceramide;    tumor-associated macrophages;   

DOI  :  10.3390/ijms19113693

来源: DOAJ

【 摘 要 】

Combined immunotherapy constitutes a novel, advanced strategy in cancer treatment. In this study, we investigated immunotherapy in the mouse TC-1/A9 model of human papillomavirus type 16 (HPV16)-associated tumors characterized by major histocompatibility complex class I (MHC-I) downregulation. We found that the induction of a significant anti-tumor response required a combination of DNA vaccination with the administration of an adjuvant, either the synthetic oligodeoxynucleotide ODN1826, carrying immunostimulatory CpG motifs, or α-galactosylceramide (α-GalCer). The most profound anti-tumor effect was achieved when these adjuvants were applied in a mix with a one-week delay relative to DNA immunization. Combined immunotherapy induced tumor infiltration with various subsets of immune cells contributing to tumor regression, of which cluster of differentiation (CD) 8⁺ T cells were the predominant subpopulation. In contrast, the numbers of tumor-associated macrophages (TAMs) were not markedly increased after immunotherapy but in vivo and in vitro results showed that they could be repolarized to an anti-tumor M1 phenotype. A blockade of T cell immunoglobulin and mucin-domain containing-3 (Tim-3) immune checkpoint had a negligible effect on anti-tumor immunity and TAMs repolarization. Our results demonstrate a benefit of combined immunotherapy comprising the activation of both adaptive and innate immunity in the treatment of tumors with reduced MHC-I expression.

【 授权许可】

Unknown