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Pre-operative intracellular glutathione levels of peripheral monocytes as a biomarker to predict survival of colorectal cancer patients

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Abstract

The ability to predict anti-tumor immune responses at local tumor growing sites using only peripheral blood specimens would be helpful in determining therapeutic options for patients with solid tumors. Here, we show that the glutathione intracellular content (icGSH) of peripheral monocytes (Mo) correlates positively with T cell infiltration within tumor islets and overall survival in patients with colorectal carcinoma. IcGSH redox status was determined in CD14+ Mo prior to surgery by staining with monochlorobimane. The tumor-infiltrating T cells (TIL) were quantified as CD45RO+ T cells in resected tumors using paraffin sections. A positive association was found between the GSH index and TIL in tumor islets (P < 0.001). The 50% cut-off value for the GSH index, that is the determinant between TIL presence or absence in tumor islets, was calculated to be almost 0.7 through logistic regression analysis. Mo with a GSH index of ≥0.7 were termed reductive (R)-Mo, and those with <0.7 were designated as oxidative (O)-Mo. Cox’s proportional hazards regression analysis of patients with R-Mo or O-Mo prior to surgery, and the presence or absence of TIL, was found to correlate significantly with the overall survival rate of stage II and III patients. Kaplan–Meier analysis also showed a significant correlation. These results indicate that the Mo icGSH index is a useful biomarker parameter for better understanding the host/tumor relationship prior to surgery, thereby enabling the development of an individual patient-oriented therapeutic strategy.

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Acknowledgments

We wish to express our deepest gratitude to Dr. Hiromi Fujiwara for his helpful contribution to the inception of this study. Finally, we would also like to thank the staff of the Louis Pasteur Center for Medical Research.

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Authors and Affiliations

  1. Louis Pasteur Center for Medical Research, 103-5, Tanakamonzen-cho, Sakyo-ku, Kyoto City, Kyoto, 606-8225, Japan

    Kazuko Uno & Katsumi Yagi

  2. Department of Surgery, Kinki University, Sayama, Osaka, Japan

    Kiyotaka Okuno

  3. Department of Cellular and Molecular Immunology, Mie University Graduate School of Medicine, Mie, Japan

    Takuma Kato

  4. Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Mie, Japan

    Saeko Tada-Oikawa

  5. Kan Clinic, Kyoto, Japan

    Norimichi Kan

  6. Weyth Discovery Res, Tokyo, Japan

    Hideo Saotome

  7. Kyoto Prefectural University of Medicine, Kyoto, Japan

    Junji Hamuro

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  1. Kazuko Uno
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  2. Kiyotaka Okuno
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  3. Takuma Kato
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  4. Saeko Tada-Oikawa
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Correspondence to Kazuko Uno.

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262_2010_868_MOESM1_ESM.tif

Supplement Fig. 1 Comparison of GSH index and amount of reductive GSH evaluated by HPLC. A positive correlation between the GSH index and the amount of reductive GSH (R = 0.78, p = 0.0044)

262_2010_868_MOESM2_ESM.tif

Supplement Fig. 2 Line histogram comparison of the GSH index of healthy subjects (straight line), non-treated preoperative colon/rectum cancer-bearing patients (dotted line) and recurrence colon/rectum cancer-bearing patients (gray line). The GSH index of Mo in tumor-bearing patients showed greater variance compared with that of Mo in healthy individuals (NS: not significant)

262_2010_868_MOESM3_ESM.tif

Supplement Fig. 3 (A) Kaplan–Meier analyses of patients with colorectal cancer (n = 30): patients with R-Mo (GSH ≥ 0.7) or O-Mo (GSH < 0.7) plotted separately (p = 0.017). (B) Kaplan–Meier analyses of patients with colorectal cancer (n = 30): patients with or without intratumoral T cells plotted separately (p = 0.017). (C) Kaplan–Meier analyses of patients with colorectal cancer based on the stage of cancer progression. (D) Schematic of the relationship between Mo status based on the GSH index, TIL presence/absence in tumor islets, and IL-12 responsiveness of CD4T and/or CD8T cells

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Uno, K., Okuno, K., Kato, T. et al. Pre-operative intracellular glutathione levels of peripheral monocytes as a biomarker to predict survival of colorectal cancer patients. Cancer Immunol Immunother 59, 1457–1465 (2010). https://doi.org/10.1007/s00262-010-0868-3

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  • DOI: https://doi.org/10.1007/s00262-010-0868-3

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