Agonist anti-CD137 mAb act on tumor endothelial cells to enhance recruitment of activated T lymphocytes.
Agonist monoclonal antibodies (mAb) to the immune costimulatory molecule CD137, also known as 4-1BB, are presently in clinical trials for cancer treatment on the basis of their costimulatory effects on primed T cells and perhaps other cells of the immune system. Here we provide evidence that CD137 is selectively expressed on the surface of tumor endothelial cells. Hypoxia upregulated CD137 on murine endothelial cells. Treatment of tumor-bearing immunocompromised Rag(-/-) mice with agonist CD137 mAb did not elicit any measurable antiangiogenic effects. In contrast, agonist mAb stimulated tumor endothelial cells, increasing cell surface expression of the adhesion molecules intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin. When adoptively transferred into mice, activated T lymphocytes derived from CD137-deficient animals entered more avidly into tumor tissue after treatment with agonist mAb. This effect could be neutralized with anti-ICAM-1 and anti-VCAM-1 blocking antibodies. Thus, stimulation of CD137 not only enhanced T-cell activation but also augmented their trafficking into malignant tissue, through direct actions on the blood vessels that irrigate the tumor. Our findings identify an additional mechanism of action that can explain the immunotherapeutic effects of agonist CD137 antibodies.
CIMA and CUN University of Navarra, Pamplona, Spain.
Asís
A
Palazón
Alvaro
A
Teijeira
Iván
I
Martínez-Forero
Sandra
S
Hervás-Stubbs
Carmen
C
Roncal
Iván
I
Peñuelas
Juan
J
Dubrot
Aizea
A
Morales-Kastresana
José Luis
JL
Pérez-Gracia
M Carmen
MC
Ochoa
Laura
L
Ochoa-Callejero
Alfredo
A
Martínez
Alfonso
A
Luque
Joseph
J
Dinchuk
Ana
A
Rouzaut
Maria
M
Jure-Kunkel
Ignacio
I
Melero
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000276:immunology / Q000628:therapy; D013601:T-Lymphocytes / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000819:agonists* / Q000096:biosynthesis / Q000276:immunology
D000911:Antibodies, Monoclonal; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9