CD4+CD25+ T regulatory cells dominate multiple immune evasion mechanisms in early but not late phases of tumor development in a B cell lymphoma model.
Tumors use a complex set of direct and indirect mechanisms to evade the immune system. Naturally arising CD4(+)CD25(+)FoxP3(+) T regulatory (Treg) cells have been implicated recently in tumor immune escape mechanism, but the relative contribution of these cells to overall tumor progression compared with other immune evasion mechanisms remains to be elucidated. Using the A20 B cell lymphoma as a transplantable tumor model, we demonstrate that this tumor employs multiple direct (expression of immunoinhibitory molecule PD-L1, IDO, and IL-10, and lack of expression of CD80 costimulatory molecule) and indirect (down-regulation of APC function and induction of Treg cells) immune evasion mechanisms. Importantly, Treg cells served as the dominant immune escape mechanism early in tumor progression because the physical elimination of these cells before tumor challenge resulted in tumor-free survival in 70% of mice, whereas their depletion in animals with established tumors had no therapeutic effect. Therefore, our data suggest that Treg cells may serve as an important therapeutic target for patients with early stages of cancer and that more vigorous combinatorial approaches simultaneously targeting multiple immune evasion as well as immunosurveillance mechanisms for the generation of a productive immune response against tumor may be required for effective immunotherapy in patients with advanced disease.
Elpek
Kutlu G
KG
Institute for Cellular Therapeutics and Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202, USA.
Lacelle
Chantale
C
Singh
Narendra P
NP
Yolcu
Esma S
ES
Shirwan
Haval
H
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D018572:Disease-Free Survival; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D008212:Lymphocyte Depletion; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D019139:Tumor Escape / Q000276:immunology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse