Mice with enhanced macrophage angiotensin-converting enzyme are resistant to melanoma.
Angiotensin-converting enzyme (ACE) is a peptidase responsible for the cleavage of angiotensin I and several other peptides. Here, gene targeting was used to switch control of the ACE locus from the endogenous promoter to the macrophage-specific c-fms promoter. Challenge of these mice, called ACE 10/10, with the aggressive mouse melanoma cell line B16 showed that they are remarkably resistant to tumor growth. Tumor resistance was seen after challenge with different melanoma cell lines and in mice with different genetic backgrounds. Histological study of the tumors that did grow in ACE 10/10 mice showed an enhanced inflammatory response. ACE 10/10 mice had increased numbers of tumor epitope-specific CD8(+) T cells after challenge with melanoma or lymphoma. ACE 10/10 macrophages showed increased production of interleukin-12 and nitric oxide but reduced interleukin-10. Engraftment of wild-type mice with ACE 10/10 bone marrow transferred B16 tumor resistance. Injection of B16 tumors with ACE 10/10 macrophages also reduced tumor growth. ACE 10/10 mice may define a new means of enhancing the immune response, which may be potentially useful in several human clinical situations.
Shen
Xiao Z
XZ
Department of Pathology and Laboratory Medicine, Emory University, 101 Woodruff Circle, Atlanta, GA 30322, USA.
Li
Ping
P
Weiss
Daiana
D
Fuchs
Sebastien
S
Xiao
Hong D
HD
Adams
Jon A
JA
Williams
Ifor R
IR
Capecchi
Mario R
MR
Taylor
W Robert
WR
Bernstein
Kenneth E
KE
D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016026:Bone Marrow Transplantation; D045744:Cell Line, Tumor; D018390:Gene Targeting; D006801:Humans; D016753:Interleukin-10 / Q000097:blood; D053762:Interleukin-12 Subunit p40 / Q000097:blood; D008264:Macrophages / Q000201:enzymology*; D008546:Melanoma, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009573:Nitrites / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D014018:Tissue Distribution
D053762:Interleukin-12 Subunit p40; D009573:Nitrites; D000808:Angiotensinogen; D016753:Interleukin-10; D012083:Renin