Targeting STAT3 in adoptively transferred T cells promotes their in vivo expansion and antitumor effects.
Adoptive cell therapy with engineered T cells to improve natural immune response and antitumor functions has shown promise for treating cancer. However, the requirement for extensive ex vivo manipulation of T cells and the immunosuppressive effects of the tumor microenvironment limit this therapeutic modality. In the present study, we investigated the possibility to circumvent these limitations by engineering Stat3 -deficient CD8(+) T cells or by targeting Stat3 in the tumor microenvironment. We show that ablating Stat3in CD8(+) T cells prior to their transfer allows their efficient tumor infiltration and robust proliferation, resulting in increased tumor antigen-specific T-cell activity and tumor growth inhibition. For potential clinical translation, we combined adoptive T-cell therapy with a Food and Drug Administration-approved tyrosine kinase inhibitor, sunitinib, in renal cell carcinoma and melanoma tumor models. Sunitinib inhibited Stat3 in dendritic cells and T cells and reduced conversion of transferred FoxP3(-) T cells to tumor-associated regulatory T cells while increasing transferred CD8(+) T-cell infiltration and activation at the tumor site, leading to inhibition of primary tumor growth. These data show that adoptively transferred T cells can be expanded and activated in vivo either by engineering Stat3-silenced T cells or by targeting Stat3 systemically with small-molecule inhibitors.
Department of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute at City of Hope, Duarte, California, USA.
Maciej
M
Kujawski
Chunyan
C
Zhang
Andreas
A
Herrmann
Karen
K
Reckamp
Anna
A
Scuto
Michael
M
Jensen
Jiehui
J
Deng
Stephen
S
Forman
Robert
R
Figlin
Hua
H
Yu
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007211:Indoles / Q000627:therapeutic use; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011758:Pyrroles / Q000627:therapeutic use; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D000077210:Sunitinib; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology
D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D050796:STAT3 Transcription Factor; D000077210:Sunitinib