Inhibiting systemic autophagy during interleukin 2 immunotherapy promotes long-term tumor regression

Xiaoyan Liang, Michael E. De Vera, William J. Buchser, Antonio Romo De Vivar Chavez, Patricia Loughran, Donna Beer Stolz, Per Basse, Tao Wang, Bennett Van Houten, Herbert J. Zeh, Michael T. Lotze

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

Administration of high-dose interleukin-2 (HDIL-2) has durable antitumor effects in 5% to 10% of patients with melanoma and renal cell carcinoma. However, treatment is often limited by side effects, including reversible, multiorgan dysfunction characterized by a cytokine-induced systemic autophagic syndrome. Here, we hypothesized that the autophagy inhibitor chloroquine would enhance IL-2 immunotherapeutic efficacy and limit toxicity. In an advanced murine metastatic liver tumor model, IL-2 inhibited tumor growth in a dose-dependent fashion. These antitumor effects were significantly enhanced upon addition of chloroquine. The combination of IL-2 with chloroquine increased long-term survival, decreased toxicity associated with vascular leakage, and enhanced immune cell proliferation and infiltration in the liver and spleen. HDIL-2 alone increased serum levels of HMGB1, IFN-γ, IL-6, and IL-18 and also induced autophagy within the liver and translocation of HMGB1 from the nucleus to the cytosol in hepatocytes, effects that were inhibited by combined administration with chloroquine. In tumor cells, chloroquine increased autophagic vacuoles and LC3-II levels inhibited oxidative phosphorylation and ATP production and promoted apoptosis, which was associated with increased Annexin-V +/propidium iodide (PI) - cells, cleaved PARP, cleaved caspase-3, and cytochrome c release from mitochondria. Taken together, our findings provide a novel clinical strategy to enhance the efficacy of HDIL-2 immunotherapy for patients with cancer.

Original languageEnglish (US)
Pages (from-to)2791-2801
Number of pages11
JournalCancer Research
Volume72
Issue number11
DOIs
StatePublished - Jun 1 2012
Externally publishedYes

Fingerprint

Autophagy
Immunotherapy
Chloroquine
Interleukin-2
HMGB1 Protein
Neoplasms
Liver
Interleukin-18
Propidium
Annexin A5
Oxidative Phosphorylation
Vacuoles
Cytochromes c
Renal Cell Carcinoma
Caspase 3
Cytosol
Blood Vessels
Hepatocytes
Melanoma
Interleukin-6

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Liang, X., De Vera, M. E., Buchser, W. J., Chavez, A. R. D. V., Loughran, P., Stolz, D. B., ... Lotze, M. T. (2012). Inhibiting systemic autophagy during interleukin 2 immunotherapy promotes long-term tumor regression. Cancer Research, 72(11), 2791-2801. https://doi.org/10.1158/0008-5472.CAN-12-0320

Inhibiting systemic autophagy during interleukin 2 immunotherapy promotes long-term tumor regression. / Liang, Xiaoyan; De Vera, Michael E.; Buchser, William J.; Chavez, Antonio Romo De Vivar; Loughran, Patricia; Stolz, Donna Beer; Basse, Per; Wang, Tao; Van Houten, Bennett; Zeh, Herbert J.; Lotze, Michael T.

In: Cancer Research, Vol. 72, No. 11, 01.06.2012, p. 2791-2801.

Research output: Contribution to journalArticle

Liang, X, De Vera, ME, Buchser, WJ, Chavez, ARDV, Loughran, P, Stolz, DB, Basse, P, Wang, T, Van Houten, B, Zeh, HJ & Lotze, MT 2012, 'Inhibiting systemic autophagy during interleukin 2 immunotherapy promotes long-term tumor regression', Cancer Research, vol. 72, no. 11, pp. 2791-2801. https://doi.org/10.1158/0008-5472.CAN-12-0320
Liang X, De Vera ME, Buchser WJ, Chavez ARDV, Loughran P, Stolz DB et al. Inhibiting systemic autophagy during interleukin 2 immunotherapy promotes long-term tumor regression. Cancer Research. 2012 Jun 1;72(11):2791-2801. https://doi.org/10.1158/0008-5472.CAN-12-0320
Liang, Xiaoyan ; De Vera, Michael E. ; Buchser, William J. ; Chavez, Antonio Romo De Vivar ; Loughran, Patricia ; Stolz, Donna Beer ; Basse, Per ; Wang, Tao ; Van Houten, Bennett ; Zeh, Herbert J. ; Lotze, Michael T. / Inhibiting systemic autophagy during interleukin 2 immunotherapy promotes long-term tumor regression. In: Cancer Research. 2012 ; Vol. 72, No. 11. pp. 2791-2801.
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