title: Tumor-specific CD4+ T cells maintain effector and memory tumor-specific CD8+ T cells.
abstract: Immunotherapies that augment antitumor T cells have had recent success for treating patients with cancer. Here we examined whether tumor-specific CD4(+) T cells enhance CD8(+) T-cell adoptive immunotherapy in a lymphopenic environment. Our model employed physiological doses of tyrosinase-related protein 1-specific CD4(+) transgenic T cells-CD4(+) T cells and pmel-CD8(+) T cells that when transferred individually were subtherapeutic; however, when transferred together provided significant (p ≤ 0.001) therapeutic efficacy. Therapeutic efficacy correlated with increased numbers of effector and memory CD8(+) T cells with tumor-specific cytokine expression. When combined with CD4(+) T cells, transfer of total (naïve and effector) or effector CD8(+) T cells were highly effective, suggesting CD4(+) T cells can help mediate therapeutic effects by maintaining function of activated CD8(+) T cells. In addition, CD4(+) T cells had a pronounced effect in the early posttransfer period, as their elimination within the first 3 days significantly (p < 0.001) reduced therapeutic efficacy. The CD8(+) T cells recovered from mice treated with both CD8(+) and CD4(+) T cells had decreased expression of PD-1 and PD-1-blockade enhanced the therapeutic efficacy of pmel-CD8 alone, suggesting that CD4(+) T cells help reduce CD8(+) T-cell exhaustion. These data support combining immunotherapies that elicit both tumor-specific CD4(+) and CD8(+) T cells for treatment of patients with cancer.
authors.affiliation: Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, USA; Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Church
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Jensen
authors.forename: Paul A
authors.initials: PA
authors.lastname: Antony
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Fox
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D019496:Cancer Vaccines / Q000276:immunology; D002450:Cell Communication; D060833:Cellular Microenvironment; D003602:Cytotoxicity, Immunologic; D005260:Female; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive / Q000379:methods* / Q000639:trends; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D010088:Oxidoreductases; C079621:Tyrp1 protein, mouse
keywords: CD4+ T-cell help; Cancer immunotherapy; Metastatic melanoma; PD-1; T cell