Mitigating Age-Related Immune Dysfunction Heightens the Efficacy of Tumor Immunotherapy in Aged Mice

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 8; pp. 2089 - 2099
• Main Authors: Hurez, Vincent, Daniel, Benjamin J., Sun, Lishi, Liu, Ai-Jie, Ludwig, Sara M., Kious, Mark J., Thibodeaux, Suzanne R., Pandeswara, Srilakshmi, Murthy, Kruthi, Livi, Carolina B., Wall, Shawna, Brumlik, Michael J., Shin, Tahiro, Zhang, Bin, Curiel, Tyler J.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.04.2012
• Subjects: Age; Aging - immunology; Animals; Antibodies; Antibodies, Monoclonal - therapeutic use; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Antitumor activity; Biological and medical sciences; Cancer; Diphtheria Toxin - therapeutic use; Disease Models, Animal; Effector cells; Flow Cytometry; Geriatrics; Immunoregulation; Immunotherapy; Immunotherapy - methods; Interleukin-2 - therapeutic use; Lymphocyte Depletion - methods; Lymphocytes T; Medical sciences; Mice; Mice, Inbred C57BL; Neoplasms, Experimental - immunology; Neoplasms, Experimental - therapy; Pharmacology. Drug treatments; Receptors, Cell Surface - antagonists & inhibitors; Recombinant Fusion Proteins - therapeutic use; Suppressor cells; T-Lymphocytes, Regulatory - immunology; Tumors; Immunopathology; Vertebrata; Mammalia; Treatment; Mouse; Animal; Treatment efficiency; Immunotherapy; Rodentia; Malignant tumor; Age; Cancer
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-11-3019

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+CD25hi 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 tumor-associated 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. Cancer Res; 72(8); 2089–99. ©2012 AACR.