The anti-tumor activity of the STAT3 inhibitor STX-0119 occurs via promotion of tumor-infiltrating lymphocyte accumulation in temozolomide-resistant glioblastoma cell line

Immunol Lett. 2017 Oct;190:20-25. doi: 10.1016/j.imlet.2017.07.005. Epub 2017 Jul 15.

Abstract

STAT3 is considered to be a key molecule to mediating tumor-induced immunosuppression in various manners at tumor sites, by acting through immune-regulatory cytokines derived from the tumor cells. Specific anti-STAT3 inhibitors have been developed using nude mouse models transplanted with human tumor cells. However, mouse systems cannot accurately represent the human immune response induced by STAT3 inhibitors, and more humanized therapeutic model based on human immune cells and tumors are needed. In the present study, an immune-deficient NOG mouse with the deletion of both MHC-class I and class II genes, an MHC-double knockout mouse (dKO-NOG), was developed and used to establish humanized immunotherapeutic model. We investigated the immunological effect of the STAT3 inhibitor STX-0119 against TMZ-resistant (TMZ-R) U87 glioma tumors by using humanized dKO-NOG mice. We compared the anti-tumor effects of STX-0119 between the nude and humanized dKO-NOG mouse models. An in vivo study using the nude mouse model showed that STX-0119 inhibited the growth of TMZR U87 tumors, but accumulation of tumor-infiltrating lymphocytes (TILs) were not promoted compared with the control levels. In contrast, STX-0119 inhibited tumor growth more rapidly and strongly in humanized dKO-NOG mice than in nude mice, and a large amount of TILs, mainly consisting of CD8+ T cells and macrophages, were found in the tumors. These results suggest that STX-0119 has anti-tumor activity occurring through the promotion of TIL accumulation at the tumor site and that humanized dKO-NOG mouse system may be a powerful tool to evaluate the effects of STAT3 inhibitors on human systems.

Keywords: Humanized NOG mouse; NOG-MHC dKO mouse; STAT3 inhibitor; TMZ-resistant glioblastoma; Tumor-infiltrating lymphocytes.

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Cell Movement
  • Dacarbazine / analogs & derivatives
  • Dacarbazine / therapeutic use
  • Drug Resistance, Neoplasm
  • Glioblastoma / drug therapy*
  • HLA-A2 Antigen / metabolism
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class II / genetics
  • Humans
  • Leukocytes, Mononuclear / immunology*
  • Leukocytes, Mononuclear / transplantation
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Mice
  • Mice, Knockout
  • Mice, Nude
  • Oxadiazoles / pharmacology
  • Oxadiazoles / therapeutic use*
  • Quinolines / pharmacology
  • Quinolines / therapeutic use*
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • Temozolomide
  • Tumor Burden
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • HLA-A*02:01 antigen
  • HLA-A2 Antigen
  • Histocompatibility Antigens Class I
  • Histocompatibility Antigens Class II
  • Oxadiazoles
  • Quinolines
  • STAT3 Transcription Factor
  • STX-0119
  • Dacarbazine
  • Temozolomide