An anti-transforming growth factor beta antibody suppresses metastasis via cooperative effects on multiple cell compartments.
Overexpression of transforming growth factor beta (TGF-beta) is frequently associated with metastasis and poor prognosis, and TGF-beta antagonism has been shown to prevent metastasis in preclinical models with surprisingly little toxicity. Here, we have used the transplantable 4T1 model of metastatic breast cancer to address underlying mechanisms. We showed that efficacy of the anti-TGF-beta antibody 1D11 in suppressing metastasis was dependent on a synergistic combination of effects on both the tumor parenchyma and microenvironment. The main outcome was a highly significant enhancement of the CD8+ T-cell-mediated antitumor immune response, but effects on the innate immune response and on angiogenesis also contributed to efficacy. Treatment with 1D11 increased infiltration of natural killer cells and T cells at the metastatic site, and enhanced expression of coactivators (NKG2D) and cytotoxic effectors (perforin and granzyme B) on CD8+ T cells. On the tumor cells, increased expression of an NKG2D ligand (Rae1gamma) and of a death receptor (TNFRSF1A) contributed to enhanced immune cell-mediated recognition and lysis. The data suggest that elevated TGF-beta expression in the tumor microenvironment modulates a complex web of intercellular interactions that aggregately promote metastasis and progression. TGF-beta antibodies reverse this effect, and the absence of a major effect of TGF-beta antagonism on any one cell compartment may be critical for a good therapeutic window and the avoidance of autoimmune complications.
Nam
Jeong-Seok
JS
Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Korea.
Terabe
Masaki
M
Mamura
Mizuko
M
Kang
Mi-Jin
MJ
Chae
Helen
H
Stuelten
Christina
C
Kohn
Ethan
E
Tang
Binwu
B
Sabzevari
Helen
H
Anver
Miriam R
MR
Lawrence
Scott
S
Danielpour
David
D
Lonning
Scott
S
Berzofsky
Jay A
JA
Wakefield
Lalage M
LM
D000818:Animals; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D007167:Immunotherapy / Q000379:methods*; D007694:Killer Cells, Natural / Q000378:metabolism; D008024:Ligands; D015674:Mammary Neoplasms, Animal / Q000378:metabolism* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D011379:Prognosis; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000737:chemistry*
D017077:Culture Media, Conditioned; D008024:Ligands; D016212:Transforming Growth Factor beta