An unbiased in vivo functional genomics screening approach in mice identifies novel tumor cell-based regulators of immune rejection.
Cancer Immunol Immunother
; 66(12): 1529-1544, 2017 Dec.
Article
in En
| MEDLINE
| ID: mdl-28770278
ABSTRACT
The clinical successes of immune checkpoint therapies for cancer make it important to identify mechanisms of resistance to anti-tumor immune responses. Numerous resistance mechanisms have been identified employing studies of single genes or pathways, thereby parsing the tumor microenvironment complexity into tractable pieces. However, this limits the potential for novel gene discovery to in vivo immune attack. To address this challenge, we developed an unbiased in vivo genome-wide RNAi screening platform that leverages host immune selection in strains of immune-competent and immunodeficient mice to select for tumor cell-based genes that regulate in vivo sensitivity to immune attack. Utilizing this approach in a syngeneic triple-negative breast cancer (TNBC) model, we identified 709 genes that selectively regulated adaptive anti-tumor immunity and focused on five genes (CD47, TGFß1, Sgpl1, Tex9 and Pex14) with the greatest impact. We validated the mechanisms that underlie the immune-related effects of expression of these genes in different TNBC lines, as well as tandem synergistic interactions. Furthermore, we demonstrate the impact of different genes with previously unknown immune functions (Tex9 and Pex14) on anti-tumor immunity. Thus, this innovative approach has utility in identifying unknown tumor-specific regulators of immune recognition in multiple settings to reveal novel targets for future immunotherapies.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Triple Negative Breast Neoplasms
/
Immunotherapy
Type of study:
Diagnostic_studies
/
Screening_studies
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Cancer Immunol Immunother
Journal subject:
ALERGIA E IMUNOLOGIA
/
NEOPLASIAS
/
TERAPEUTICA
Year:
2017
Document type:
Article
Affiliation country:
United States