Importance of signaling via the IFN-alpha/beta receptor on host cells for the realization of the therapeutic benefits of cyclophosphamide for mice bearing a large MOPC-315 tumor.
Here we show that low-dose cyclophosphamide (CY), that depends for its therapeutic effectiveness on the immunopotentiating activity of the drug for T cell-mediated tumor-eradicating immunity, is curative for approximately 80% of wild-type (WT) mice bearing a large s.c. MOPC-315 tumor, but only for approximately 10% of IFN-alpha/betaR-/- mice bearing a large s.c. MOPC-315 tumor. Histopathological examination of the s.c. tumors of such mice on day 4 after the chemotherapy revealed that the low dose of CY led to accumulation of T lymphocytes in both the WT and the IFN-alpha/betaR-/- mice. However, in the CY treated tumor bearing WT mice the T lymphocytes were present throughout the tumor mass and in direct contact with tumor cells, but in the CY treated tumor bearing IFN-alpha/betaR-/- mice most of the T lymphocytes remained in blood vessels. In addition to being important for CY-induced transendothelial migration of T lymphocytes into the tumor mass, we show here that signaling via the IFN-alpha/betaR is also important for CY-induced control of metastatic tumor progression in the spleen and liver of the tumor bearing mice. Finally, CY cured tumor bearing WT mice were resistant to a subsequent challenge with MOPC-315 tumor cells, but the few CY cured tumor bearing IFN-alpha/betaR-/- mice were not. Thus, signaling via the IFN-alpha/betaR on host cells in MOPC-315 tumor bearers is important for CY-induced: (a) transendothelial migration of T lymphocytes into the tumor mass and the eradication of the primary tumor, (b) control of metastatic tumor progression, and (c) resistance to a subsequent tumor challenge.
Mokyr
Margalit B
MB
Department of Biochemistry and Molecular Genetics (M/C 536), University of Illinois, 1819 West Polk Street, Chicago, IL, 60612, USA. mokyr@uic.edu
Place
Aaron T
AT
Artwohl
James E
JE
Valli
V E Ted
VE
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D002465:Cell Movement; D003520:Cyclophosphamide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007111:Immunity, Cellular; D008565:Membrane Proteins / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D010954:Plasmacytoma / Q000276:immunology* / Q000628:therapy*; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
D018906:Antineoplastic Agents, Alkylating; D008565:Membrane Proteins; D017471:Receptors, Interferon; D053633:Receptor, Interferon alpha-beta; D003520:Cyclophosphamide