Inhibition of host signal transducer and activator of transcription factor 6 results in cure with cyclophosphamide and interleukin 12 immunotherapy.
BACKGROUND
Interleukin (IL)-12 immunotherapy is highly effective against established immunogenic tumors. However, nonimmunogenic tumors fail to respond to IL-12 therapy. Analysis of tumor rejection of the immunogenic tumors shows that a preexisting antitumor immune response is required for an effective IL-12 response. It is not known whether this lack of a preexisting host antitumor immune response is a limiting factor for the lack of response to IL-12 therapy by nonimmunogenic tumors.


METHODS
Experiments were done using the spontaneously arising nonimmunogenic metastatic murine breast 4T1 carcinoma in normal and STAT6 knockout BALB/c mice.


RESULTS
4T1 is nonimmunogenic in normal mice, and established subcutaneous tumors are resistant to immunotherapy with cyclophosphamide (Cy) plus IL-12. However, in STAT6 knockout mice, 4T1 becomes immunogenic, and established 4T1 tumors are eradicated by Cy plus IL-12. Adoptive transfer of spleen cells from normal mice into STAT6 knockout mice before tumor inoculation reduces both the immunogenicity and response to Cy plus IL-12 immunotherapy of 4T1 in the recipient mice.


CONCLUSIONS
Cy plus IL-12 immunotherapy can eradicate nonimmunogenic tumors as long as a preexisting immunity is established in the tumor-bearing host. Furthermore, the STAT6 pathway is likely involved in the suppression of the development of host antitumor immunity.
Norton
Jeffrey A
JA
Department of Surgery, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California, 94305-5641, USA. janorton@stanford.edu
Li
Michelle
M
Lee
Natalie C
NC
Tsung
Kangla
K
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D003520:Cyclophosphamide / Q000494:pharmacology*; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive; D018664:Interleukin-12 / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000188:drug therapy; D015398:Signal Transduction; D014157:Transcription Factors / Q000187:drug effects*
D014157:Transcription Factors; D018664:Interleukin-12; D003520:Cyclophosphamide