title: Bystander activation and anti-tumor effects of CD8+ T cells following Interleukin-2 based immunotherapy is independent of CD4+ T cell help.
abstract: We have previously demonstrated that immunotherapy combining agonistic anti-CD40 and IL-2 (IT) results in synergistic anti-tumor effects. IT induces expansion of highly cytolytic, antigen-independent "bystander-activated" (CD8(+)CD44high) T cells displaying a CD25(-)NKG2D(+) phenotype in a cytokine dependent manner, which were responsible for the anti-tumor effects. While much attention has focused on CD4(+) T cell help for antigen-specific CD8(+) T cell expansion, little is known regarding the role of CD4(+) T cells in antigen-nonspecific bystander-memory CD8(+) T cell expansion. Utilizing CD4 deficient mouse models, we observed a significant expansion of bystander-memory T cells following IT which was similar to the non-CD4 depleted mice. Expanded bystander-memory CD8(+) T cells upregulated PD-1 in the absence of CD4(+) T cells which has been published as a hallmark of exhaustion and dysfunction in helpless CD8(+) T cells. Interestingly, compared to CD8(+) T cells from CD4 replete hosts, these bystander expanded cells displayed comparable (or enhanced) cytokine production, lytic ability, and in vivo anti-tumor effects suggesting no functional impairment or exhaustion and were enriched in an effector phenotype. There was no acceleration of the post-IT contraction phase of the bystander memory CD8(+) response in CD4-depleted mice. The response was independent of IL-21 signaling. These results suggest that, in contrast to antigen-specific CD8(+) T cell expansion, CD4(+) T cell help is not necessary for expansion and activation of antigen-nonspecific bystander-memory CD8(+) T cells following IT, but may play a role in regulating conversion of these cells from a central memory to effector phenotype. Additionally, the expression of PD-1 in this model appears to be a marker of effector function and not exhaustion.
authors.affiliation: Department of Radiation Oncology School of Medicine, University of California Davis, Sacramento, California, United States of America.
authors.forename: Arta M
authors.initials: AM
authors.lastname: Monjazeb
authors.affiliation: Department of Dermatology, School of Medicine, University of California Davis, Sacramento, California, United States of America.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Tietze
authors.affiliation: Department of Dermatology, School of Medicine, University of California Davis, Sacramento, California, United States of America.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Grossenbacher
authors.affiliation: Department of Dermatology, School of Medicine, University of California Davis, Sacramento, California, United States of America.
authors.forename: Hui-Hua
authors.initials: HH
authors.lastname: Hsiao
authors.affiliation: Department of Dermatology, School of Medicine, University of California Davis, Sacramento, California, United States of America.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Zamora
authors.affiliation: Department of Dermatology, School of Medicine, University of California Davis, Sacramento, California, United States of America.
authors.forename: Annie
authors.initials: A
authors.lastname: Mirsoian
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation and Masonic Cancer Center, University of Minnesota, Minneapolis, Massachusetts, United States of America.
authors.forename: Brent
authors.initials: B
authors.lastname: Koehn
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation and Masonic Cancer Center, University of Minnesota, Minneapolis, Massachusetts, United States of America.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland, United States of America.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Weiss
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland, United States of America.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Wiltrout
authors.affiliation: Department of Dermatology, School of Medicine, University of California Davis, Sacramento, California, United States of America.
authors.forename: Gail D
authors.initials: GD
authors.lastname: Sckisel
authors.affiliation: Department of Dermatology, School of Medicine, University of California Davis, Sacramento, California, United States of America; Department of Internal Medicine, School of Medicine, University of California, Davis, Sacramento, California, United States of America.
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D015704:CD4 Antigens / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019013:CD40 Antigens / Q000008:administration & dosage / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D007167:Immunotherapy; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology*; D007378:Interleukins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D015398:Signal Transduction; D000098546:Interleukin-21
chemical_list: D015704:CD4 Antigens; D019013:CD40 Antigens; D016207:Cytokines; D007376:Interleukin-2; D007378:Interleukins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D000098546:Interleukin-21