Transforming growth factor-beta receptor blockade augments the effectiveness of adoptive T-cell therapy of established solid cancers.
OBJECTIVE
Adoptive cellular immunotherapy is a promising approach to eradicate established tumors. However, a significant hurdle in the success of cellular immunotherapy involves recently identified mechanisms of immune suppression on cytotoxic T cells at the effector phase. Transforming growth factor-beta (TGF-beta) is one of the most important of these immunosuppressive factors because it affects both T-cell and macrophage functions. We thus hypothesized that systemic blockade of TGF-beta signaling combined with adoptive T-cell transfer would enhance the effectiveness of the therapy.


METHODS
Flank tumors were generated in mice using the chicken ovalbumin-expressing thymoma cell line, EG7. Splenocytes from transgenic OT-1 mice (whose CD8 T cells recognize an immunodominant peptide in chicken ovalbumin) were activated in vitro and adoptively transferred into mice bearing large tumors in the presence or absence of an orally available TGF-beta receptor-I kinase blocker (SM16).


RESULTS
We observed markedly smaller tumors in the group receiving the combination of SM16 chow and adoptive transfer. Additional investigation revealed that TGF-beta receptor blockade increased the persistence of adoptively transferred T cells in the spleen and lymph nodes, increased numbers of adoptively transferred T cells within tumors, increased activation of these infiltrating T cells, and altered the tumor microenvironment with a significant increase in tumor necrosis factor-alpha and decrease in arginase mRNA expression.


CONCLUSIONS
We found that systemic blockade of TGF-beta receptor activity augmented the antitumor activity of adoptively transferred T cells and may thus be a useful adjunct in future clinical trials.
Wallace
Africa
A
Thoracic Oncology Research Laboratory, University of Pennsylvania, Pennsylvania, USA.
Kapoor
Veena
V
Sun
Jing
J
Mrass
Paul
P
Weninger
Wolfgang
W
Heitjan
Daniel F
DF
June
Carl
C
Kaiser
Larry R
LR
Ling
Leona E
LE
Albelda
Steven M
SM
D000818:Animals; D053961:Azabicyclo Compounds / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D003131:Combined Modality Therapy; D004353:Drug Evaluation, Preclinical; D005260:Female; D016219:Immunotherapy, Adoptive; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured
D053961:Azabicyclo Compounds; D018125:Receptors, Transforming Growth Factor beta; C528106:SM16 compound