Experimental antibody therapy of liver metastases reveals functional redundancy between Fc gammaRI and Fc gammaRIV.
Many patients with colorectal cancer will develop liver metastases, even after successful surgical removal of the primary tumor at a time at which no visible metastases are present. We previously demonstrated that surgery--although mandatory--paradoxically enhances the risk of developing liver metastases. Because Ab therapy has been acknowledged as a successful strategy to treat malignancies, we studied the potential of postoperative adjuvant Ab therapy to prevent outgrowth of liver metastases. Treatment with murine anti-gp75 (TA99) mAb completely prevented outgrowth of B16F10 liver metastases in over 90% of mice. Therapeutic efficacy was maintained in either C1q- or complement receptor 3-deficient mice but was completely abrogated in FcR gamma-chain knockout mice. This indicates that the classical complement pathway was not essential, but interaction with activatory Fc gammaR was necessary for successful therapy. TA99-treatment was still effective in Fc gammaRI(-/-), Fc gammaRIII(-/-), Fc gammaRI/III(-/-), and Fc gammaRI/II/III(-/-) mice, suggesting an important role for Fc gammaRIV. However, wild-type mice that were treated with TA99 Abs and an Fc gammaRIV blocking Ab (mAb 9E9) were protected against development of liver metastases as well. Only when both Fc gammaRI and Fc gammaRIV functions were simultaneously inhibited, TA99-mediated curative Ab treatment was abrogated, indicating functional redundancy between both IgG receptors in the liver. Furthermore, depletion of liver macrophages (Kupffer cells) reduced the efficacy of Ab therapy, supporting that Kupffer cells are involved as effector cells. Importantly, since Ab treatment almost completely prevented development of liver metastases, postoperative adjuvant Ab therapy may help to improve patient prognosis.
Otten
Marielle A
MA
Immunotherapy Laboratory, Department of Immunology, University Medical Center, Utrecht, The Netherlands.
van der Bij
Gerben J
GJ
Verbeek
Sjef J
SJ
Nimmerjahn
Falk
F
Ravetch
Jeffrey V
JV
Beelen
Robert H J
RH
van de Winkel
Jan G J
JG
van Egmond
Marjolein
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000473:pathology; D005434:Flow Cytometry; D007728:Kupffer Cells / Q000276:immunology / Q000378:metabolism; D008113:Liver Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D051379:Mice; D018345:Mice, Knockout; D017452:Receptors, IgG / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; C485701:Fcgr1 protein, mouse; C522404:Fcgr4 protein, mouse; D017452:Receptors, IgG