Stat3 inhibition augments the immunogenicity of B-cell lymphoma cells, leading to effective antitumor immunity.
Mantle cell lymphoma (MCL) is an aggressive and incurable subtype of B-cell non-Hodgkin lymphomas. Although patients often respond initially to first-line treatment with chemotherapy plus monoclonal antibodies, relapse and decreased response to further lines of treatment eventually occurs. Harnessing the immune system to elicit its exquisite specificity and long-lasting protection might provide sustained MCL immunity that could potentially eradicate residual malignant cells responsible for disease relapse. Here, we show that genetic or pharmacologic disruption of Stat3 in malignant B cells augments their immunogenicity leading to better activation of antigen-specific CD4(+) T cells and restoration of responsiveness of tolerized T cells. In addition, treatment of MCL-bearing mice with a specific Stat3 inhibitor resulted in decreased Stat3 phosphorylation in malignant B cells and anti-lymphoma immunity in vivo. Our findings therefore indicate that Stat3 inhibition may represent a therapeutic strategy to overcome tolerance to tumor antigens and elicit a strong immunity against MCL and other B-cell malignancies.
Departments of Malignant Hematology, Drug Discovery, and Hematopathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
Fengdong
F
Cheng
Hongwei
H
Wang
Pedro
P
Horna
Zi
Z
Wang
Bijal
B
Shah
Eva
E
Sahakian
Karrune V
KV
Woan
Alejandro
A
Villagra
Javier
J
Pinilla-Ibarz
Said
S
Sebti
Mitchell
M
Smith
Jianguo
J
Tao
Eduardo M
EM
Sotomayor
D056704:Adaptive Immunity; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D045744:Cell Line, Tumor; D017606:Chlorine Compounds / Q000008:administration & dosage / Q000494:pharmacology; D018450:Disease Progression; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D017671:Platinum Compounds / Q000008:administration & dosage / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology
D000951:Antigens, Neoplasm; D017606:Chlorine Compounds; D017671:Platinum Compounds; D050796:STAT3 Transcription Factor; C529200:trichloronitritodiammineplatinum(IV)