Expression of a soluble transforming growth factor-beta (TGFbeta) receptor reduces tumorigenicity by regulating natural killer (NK) cell activity against 9L gliosarcoma in vivo.
Immunotherapy of gliomas has been forwarded as an attractive alternative to standard therapeutic modalities. Numerous observations indicate some therapeutic efficacy with this approach, but it is not curative in most reports. It is well established that gliomas suppress immune reactivity via a number of mechanisms, including expression CD95 ligand (CD95L), which induces apoptosis of immune effector cells, and secretion of immunosuppressive factors such as transforming growth factor-beta (TGFbeta). It has been hypothesized that abrogation of production or function of TGFbeta would improve immune reactivity to gliomas. To investigate this in a fashion that is translatable into clinical practice, we utilized a retroviral vector encoding a truncated, soluble form of the Type II receptor for TGFbeta (TFGbeta sr) and expressed it in the rat 9L gliosarcoma line (9L-TGFbeta sr). We then determined whether expression of TGFbeta sr affected in vitro sensitivity of 9L to lysis by immune effector cells, whether expression of TGFbeta sr affected tumorigenesis of 9L in vivo, and whether TGFbeta sr affected expression of immunity to 9L. In these experiments, we determined that 9L-TGFbeta sr was more susceptible than sham transfected 9L (9L-neo) to lysis by natural killer (NK) cells. We also determined that subcutaneously implanted 9L-TGFbeta sr was less tumorigenic than 9L-neo in syngeneic rats. Similarly, survival was extended by approximately 40% in rats given intracranial 9L-TGFbeta sr compared to 9L-neo. Finally, we determined that elimination of CD161+ cells resulted in comparable growth of 9L-neo and 9L-TGFbeta sr in vivo, indicating that NK or NK-like cells were responsible for the anti-tumor effects in this model.
Witham
Timothy F
TF
Brain Tumor Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213-1863, USA.
Villa
Lorissa
L
Yang
Tianbing
T
Pollack
Ian F
IF
Okada
Hideho
H
Robbins
Paul D
PD
Chambers
William H
WH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000954:Antigens, Surface / Q000276:immunology; D001932:Brain Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D018316:Gliosarcoma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology; D055651:NK Cell Lectin-Like Receptor Subfamily B; D051381:Rats; D011916:Rats, Inbred F344; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000378:metabolism*; D012878:Skin Neoplasms / Q000473:pathology; D012995:Solubility; D016019:Survival Analysis; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053781:Transforming Growth Factor beta2
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2