title: Cancer vaccination drives Nanog-dependent evolution of tumor cells toward an immune-resistant and stem-like phenotype.
abstract: Due to the exquisite specificity and potency of the immune system, vaccination is in theory the most precise and powerful approach for controlling cancer. However, current data from clinical trials indicate that vaccination rarely yields significant benefits for cancer patients in terms of tumor progression and long-term survival. The poor clinical outcomes of vaccination are primarily caused by mechanisms of immune tolerance, especially within the tumor microenvironment. Here, we report that vaccination drives the evolution of tumor cells toward an immune-resistant and stem-like phenotype that promotes tumor growth and nullifies the CTL response. The emergence of this phenotype required the transcription factor Nanog, which is induced as a consequence of immune selection. Nanog expression enhanced the stem-like features of tumor cells and protected them from killing by tumor-reactive CTLs. Delivery of siNanog into tumor-bearing mice rendered the tumor vulnerable to immune surveillance and strongly suppressed its growth. Together, our findings show tumor adaptation to vaccination through gain of an immune-resistant, stem-like phenotype and identify Nanog as a central molecular target in this process. Future vaccination technology should consider Nanog an important target to enhance the immunotherapeutic response.
authors.affiliation: Divison of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, South Korea.
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Noh
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Lee
authors.forename: Ju-Hong
authors.initials: JH
authors.lastname: Jeon
authors.forename: Tae Heung
authors.initials: TH
authors.lastname: Kang
authors.forename: Chih-Ping
authors.initials: CP
authors.lastname: Mao
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Kim
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D005260:Female; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D008810:Mice, Inbred C57BL; D000071317:Nanog Homeobox Protein; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010641:Phenotype; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014611:Vaccination
chemical_list: D019496:Cancer Vaccines; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse