Human inflammatory cells within the tumor microenvironment of lung tumor xenografts mediate tumor growth suppression in situ that depends on and is augmented by interleukin-12.
The human tumor microenvironment includes a mixture of tumor cells, inflammatory cells, fibroblasts, and endothelial cells, all of which are tethered to an extracellular matrix. It has been difficult to study the dynamic interactions of these cells in human tumors in situ for obvious ethical and logistical considerations that prohibit experimental manipulations of tumors while still in patients. Fresh tissue from human lung tumor biopsy implanted into SCID mice was shown to remain viable, and the histologic appearance of the tumor microenvironment was maintained in the tumor xenografts for at least 3 months. In this study, the authors established that the inflammatory cells within human tumor xenografts can suppress tumor growth, and that this suppression is a result, in part, of endogenously produced interleukin-12 (IL-12) because IL-12 neutralizing antibodies enhance the growth of the tumor xenografts. The tumor-inhibitory activity of the inflammatory leukocytes is also enhanced by the local and sustained release of human recombinant IL-12 into the tumor microenvironment from cytokine-loaded biodegradable microspheres. Neither the anti-IL-12 neutralizing antibody nor the delivery of exogenous IL-12 from microspheres had any effect on tumor xenografts in the absence of the inflammatory leukocytes. In conclusion, the inflammatory cells within the tumor microenvironment of human lung tumor xenografts are functional and can suppress tumor growth, and the dynamic effects of the inflammatory cells can be modulated by exogenous cytokines.
Sugiyama
Y
Y
Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Kato
M
M
Chen
F A
FA
Williams
S S
SS
Kawaguchi
Y
Y
Miya
K
K
Jong
Y S
YS
Mathiowitz
E
E
Egilmez
N K
NK
Bankert
R B
RB
D000276:Adjuvants, Immunologic / Q000235:genetics / Q000502:physiology*; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000473:pathology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D006131:Growth Inhibitors / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D008168:Lung / Q000254:growth & development / Q000276:immunology / Q000473:pathology*; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D011994:Recombinant Proteins / Q000494:pharmacology; D014183:Transplantation, Heterologous / Q000276:immunology* / Q000473:pathology
D000276:Adjuvants, Immunologic; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D011994:Recombinant Proteins; D018664:Interleukin-12