Intratumoral interleukin-21 increases antitumor immunity, tumor-infiltrating CD8+ T-cell density and activity, and enlarges draining lymph nodes.
Interleukin (IL)-21 is a novel cytokine in clinical development for the treatment of cancer. In this study, we have compared the efficacy of subcutaneous and intratumoral (IT) administration of IL-21 protein in two syngeneic mouse tumor models, RenCa renal cell carcinoma and B16 melanoma, and investigated the mechanisms by which IL-21 enhances CD8 T-cell-mediated antitumor immunity. We found that in comparison to subcutaneous administration, IT administration of IL-21 more potently inhibited tumor growth and increased survival. This correlated with increased densities of tumor-infiltrating CD8 and CD4CD25 T cells, but not CD4CD25FoxP3 T cells. Furthermore, IT administration of IL-21 increased degranulation, and expression of interferon-gamma and granzyme B in tumor-infiltrating CD8 T cells. Tumors injected with IL-21 grew slower than contralateral tumors, suggesting that the increased efficacy of IT administration of IL-21 was due to a local rather than systemic effect. IT administration of IL-21 led to enlarged tumor-draining lymph nodes (LNs), with increased naive lymphocyte numbers and proliferation of activated lymphocytes, suggesting that local administration of IL-21 generally benefits the tumor microenvironment and activates tumor-draining LNs. Overall, our data suggest that IL-21 augments CD8 T-cell-mediated antitumor immunity through increased proliferation and effector function and acts both on tumor-infiltrating CD8 T cells as well as on the draining LNs. IT administration led to superior CD8 T-cell proliferation, effector function, and antitumor efficacy, suggesting that IT administration of IL-21 may be clinically useful in patients with unresectable tumors.
Søndergaard
Henrik
H
Novo Nordisk A/S, Måløv, Denmark. hris@novonordisk.com
Galsgaard
Elisabeth D
ED
Bartholomaeussen
Monica
M
Straten
Per Thor
PT
Odum
Niels
N
Skak
Kresten
K
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053804:Granzymes / Q000378:metabolism; D007109:Immunity / Q000187:drug effects*; D015552:Injections, Intralesional; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000378:metabolism; D007378:Interleukins / Q000008:administration & dosage / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D013997:Time Factors; D016896:Treatment Outcome; D000098546:Interleukin-21
D007378:Interleukins; D007371:Interferon-gamma; D053804:Granzymes; D000098546:Interleukin-21