Potent anti-tumor killing activity of the multifunctional Treg cell line HOZOT against human tumors with diverse origins

Our plain-English summary of Potent anti-tumor killing activity of the multifunctional Treg cell line HOZOT against human tumors with diverse origins, by T. Inoue, Y. Tashiro, M. Takeuchi, et al (International Journal of Oncology, 2011).

The study

• Authors: T. Inoue, Y. Tashiro, M. Takeuchi, T. Otani, K. Tsuji-Takayama, A. Okochi, Y. Mukae, M. Koreishi, F. Yamasaki, H. Kumon, S. Nakamura, M. Kibata, E. Kondo
• Journal: International Journal of Oncology
• Published: 2011;38(5):1299-306
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The T cell line HOZOT has a unique FOXP3+CD4+ CD8+CD25+ phenotype, exhibits suppressive activity in allogeneic mixed lymphocyte reactions (MLR), and produces IL-10, defining HOZOT as regulatory T cells (Tregs). Interestingly, in addition to possessing a suppressive Treg ability, HOZOT was also found to show cytotoxicity against certain representative human cancer cell types. In order to disclose the range of anti-tumor activity by HOZOT, we screened it by using a panel of twenty human tumor cell lines with different origins. Consequently, HOZOT showed potent cytocidal effects against a wide spectrum of neoplastic cells including carcinomas, sarcomas, mesotheliomas and glioblastomas except for hematopoietic malignancies. Its anti-tumor activity was strong enough with an E:T ratio of 4:1, which is considered to be more effective than that by conventional CTLs. Furthermore, an in vivo representative mouse tumor model by implanting human colon adenocarcinoma cells revealed that adoptive transfer of HOZOT almost completely eradicated disseminated lesions on peritoneum, markedly reduced metastases in lung and liver, and dramatically decreased bloody ascites caused by peritoneal carcinomatosis. Treatment of the tumor model mice by HOZOT with an E:T ratio of 2:1 even indicated the prolongation of their survival, although not reaching obvious statistical significance. In vitro blocking experiments using antibodies and inhibitors suggested that the cytotoxic mechanism of HOZOT against tumors is different from conventional cytotoxic cells such as CTL, NK or NKT cells. Altogether, our studies demonstrated the potent killing activity of HOZOT against a broad range of human malignancies, which indicates that HOZOT is a powerful tool in immunotherapy for advanced stage tumors.

In plain English

This was a laboratory and animal study, not a study of asbestos exposure or of people. The authors tested HOZOT, a regulatory T cell line they had grown from umbilical cord blood, against a panel of human tumor cell lines. The panel included four malignant mesothelioma cell lines (H28, MSTO-211H, H2052 and H2452). With four HOZOT cells per tumor cell, killing of tumor cells ranged from 35 to 98%, mostly above 70%. One ovarian line (JHOS-2) was the exception. Three mesothelioma lines and one hepatocellular carcinoma line showed lower killing (35-50%). Normal human skin fibroblasts were not killed. In mice given human colon cancer cells in the abdomen, HOZOT treatment almost cleared tumor from the peritoneal cavity, reduced lung lesions, and left almost no bloody ascites. Untreated mice averaged 4.08 ml of ascites and CD4+ T cell-treated mice 2.14 ml (n=10). Survival was not significantly different from untreated mice. The authors concluded that HOZOT killed a broad range of human tumor types.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) cell-killing experiments plus a mouse xenograft experiment
• Who was studied: Human tumor cell lines of various origins, including four malignant mesothelioma cell lines, with normal human dermal fibroblasts (NHDF) as a normal-cell control. Also female 5-week-old NOD/SCID mice implanted in the peritoneal cavity with the human colon adenocarcinoma line WiDr. Research was done in Japan.
• Exposure: No asbestos exposure was studied. The treatment tested was the HOZOT T cell line, given at various effector-to-target (E:T) ratios in culture. In mice it was injected into the peritoneal cavity.
• Main results:
  • At an E:T ratio of 4:1, cytotoxicity against the tumor cell lines ranged from 35 to 98%, and most lines were above 70%.
  • The only tested tumor line without considerable cytotoxicity at 4:1 was the ovarian line JHOS-2.
  • Three of the mesothelioma cell lines and one hepatocellular carcinoma line showed lower cytotoxicity (35-50%) than the other cancers.
  • At an E:T ratio of 8:1, HOZOT did not kill normal human dermal fibroblasts. It killed more than 90% of WiDr, MCF-7 and U2OS tumor cells.
  • HOZOT did not kill blood-cancer (leukemia and lymphoma) cell lines. These data were not shown in the article.
  • In WiDr-bearing mice, HOZOT treatment almost completely eradicated tumor cells in the peritoneal cavity, with no accumulation of tumor ascites.
  • In HOZOT-treated mice, lung lesions were fewer and smaller than in untreated mice.
  • No liver foci were seen in HOZOT-treated mice.
  • Untreated mice averaged 4.08 ml of ascites and CD4+ T cell-treated mice averaged 2.14 ml (n=10). HOZOT-treated mice showed almost no bloody ascites.
  • Survival did not differ significantly between HOZOT-treated and untreated mice.
  • Survival was significantly higher in HOZOT-treated mice than in CD4+ T cell-treated mice (P=0.017).
  • None of the neutralizing antibodies tested significantly blocked HOZOT's killing of WiDr cells.
  • Inhibitors of PI3K, ERK1/2, JNK and Src family kinase reduced HOZOT's killing by 17.9%, 27.8%, 23.4% and 58.1% respectively.
• The authors' conclusion: The authors concluded that HOZOT showed potent killing activity against a broad range of human tumor types. They said its mechanisms seemed distinct from those of CTL, NK or NKT cells, and that it has potential as an immunotherapy effector.
• Limitations the authors state:
  • The authors said further study is needed of HOZOT's effects on normal (non-cancer) cells.
  • The authors attributed the lack of a significant survival benefit over untreated mice to tumor cells leaking under the skin at injection. Those tumors enlarged and caused the mice's deaths.
  • The authors stated that the details of the killing mechanism remain unclear.

Topics

Medical terms in this study, explained in our Lexicon: Carcinoma, Sarcoma, Mesothelioma, Adenocarcinoma, Peritoneum, Ascites, Statistical Significance, Immunotherapy.

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