Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies.
Identifying key factors that enhance immune responses is crucial for manipulating immunity to tumors. We show that after a vaccine-induced immune response, adjuvant interleukin-7 (IL-7) improves antitumor responses and survival in an animal model. The improved immune response is associated with increased IL-6 production and augmented T helper type 17 cell differentiation. Furthermore, IL-7 modulates the expression of two ubiquitin ligases: Casitas B-lineage lymphoma b (Cbl-b), a negative regulator of T cell activation, is repressed, and SMAD-specific E3 ubiquitin protein ligase-2 (Smurf2) is enhanced, which antagonizes transforming growth factor-beta signaling. Notably, we show that although short term IL-7 therapy potently enhances vaccine-mediated immunity, in the absence of vaccination it is inefficient in promoting antitumor immune responses, despite inducing homeostatic proliferation of T cells. The ability of adjuvant IL-7 to antagonize inhibitory networks at the cellular and molecular level has major implications for immunotherapy in the treatment of tumors.
Pellegrini
Marc
M
The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada.
Calzascia
Thomas
T
Elford
Alisha R
AR
Shahinian
Arda
A
Lin
Amy E
AE
Dissanayake
Dilan
D
Dhanji
Salim
S
Nguyen
Linh T
LT
Gronski
Matthew A
MA
Morre
Michel
M
Assouline
Brigitte
B
Lahl
Katharina
K
Sparwasser
Tim
T
Ohashi
Pamela S
PS
Mak
Tak W
TW
D000818:Animals; D051379:Mice; D001117:Arenaviridae Infections / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D007167:Immunotherapy / Q000379:methods; D015851:Interleukin-7 / Q000627:therapeutic use; D018655:Lymphocyte Count; D008216:Lymphocytic Choriomeningitis / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D009369:Neoplasms / Q000276:immunology; D009374:Neoplasms, Experimental / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D019496:Cancer Vaccines; D015851:Interleukin-7