title: Mitigating age-related immune dysfunction heightens the efficacy of tumor immunotherapy in aged mice.
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 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.
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, Adult Cancer Program STRF MC8252, San Antonio, Texas 78229, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Hurez
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Daniel
authors.forename: Lishi
authors.initials: L
authors.lastname: Sun
authors.forename: Ai-Jie
authors.initials: AJ
authors.lastname: Liu
authors.forename: Sara M
authors.initials: SM
authors.lastname: Ludwig
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Kious
authors.forename: Suzanne R
authors.initials: SR
authors.lastname: Thibodeaux
authors.forename: Srilakshmi
authors.initials: S
authors.lastname: Pandeswara
authors.forename: Kruthi
authors.initials: K
authors.lastname: Murthy
authors.forename: Carolina B
authors.initials: CB
authors.lastname: Livi
authors.forename: Shawna
authors.initials: S
authors.lastname: Wall
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Brumlik
authors.forename: Tahiro
authors.initials: T
authors.lastname: Shin
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Curiel
mesh_terms: D000375:Aging / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D004167:Diphtheria Toxin / Q000627:therapeutic use; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000627:therapeutic use; D008212:Lymphocyte Depletion / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004167:Diphtheria Toxin; D007376:Interleukin-2; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C551746:granulocyte receptor 1, mouse; C078456:denileukin diftitox