Mitigating age-related immune dysfunction heightens the efficacy of tumor immunotherapy in aged mice

Vincent Hurez, Benjamin J. Daniel, Lishi Sun, Ai Jie Liu, Sara M. Ludwig, Mark J. Kious, Suzanne R. Thibodeaux, Srilakshmi Pandeswara, Kruthi Murthy, Carolina B. Livi, Shawna Wall, Michael J. Brumlik, Tahiro Shin, Bin Zhang, Tyler J. Curiel*

*Corresponding author for this work

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

Although cancer tends to affect the elderly, most preclinical studies are carried out in young subjects. In this study, we developed a melanoma-specific cancer immunotherapy that shows efficacy in aged but not young hosts by mitigating age-specific tumor-associated immune dysfunction. Both young and aged CD4 +CD25 hi regulatory T cells (Treg) exhibited equivalent in vitro T-cell suppression and tumor-associated augmentation in numbers. However, denileukin diftitox (DT)-mediated Treg depletion improved tumor-specific immunity and was clinically effective only in young mice. DT-mediated Treg depletion significantly increased myeloid-derived suppressor cell (MDSC) numbers in aged but not young mice, and MDSC depletion improved tumor-specific immunity and reduced tumor growth in aged mice. Combining Treg depletion with anti-Gr-1 antibody was immunologically and clinically more efficacious than anti-Gr-1 antibody alone in aged B16-bearing mice, similar to Treg depletion alone in young mice. In contrast, DT increased MDSCs in young and aged mice following MC-38 tumor challenge, although effects were greater in aged mice. Anti-Gr-1 boosted DT effects in young but not aged mice. Aged antitumor immune effector cells are therefore competent to combat tumor when underlying tumorassociated immune dysfunction is appropriately mitigated, but this dysfunction varies with tumor, thus also varying responses to immunotherapy. By tailoring immunotherapy to account for age-related tumor-associated immune dysfunctions, cancer immunotherapy for aged patients with specific tumors can be remarkably improved.

Original languageEnglish (US)
Pages (from-to)2089-2099
Number of pages11
JournalCancer Research
Volume72
Issue number8
DOIs
StatePublished - Apr 15 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Hurez, V., Daniel, B. J., Sun, L., Liu, A. J., Ludwig, S. M., Kious, M. J., Thibodeaux, S. R., Pandeswara, S., Murthy, K., Livi, C. B., Wall, S., Brumlik, M. J., Shin, T., Zhang, B., & Curiel, T. J. (2012). Mitigating age-related immune dysfunction heightens the efficacy of tumor immunotherapy in aged mice. Cancer Research, 72(8), 2089-2099. https://doi.org/10.1158/0008-5472.CAN-11-3019