TY - JOUR

T1 - Intratumoral interleukin-21 increases antitumor immunity, tumor-infiltrating CD8+ T-cell density and activity, and enlarges draining lymph nodes

AU - Søndergaard, Henrik

AU - Galsgaard, Elisabeth D

AU - Bartholomaeussen, Monica

AU - Straten, Per Thor

AU - Ødum, Niels

AU - Skak, Kresten

N1 - Keywords: Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cell Proliferation; Granzymes; Immunity; Injections, Intralesional; Injections, Subcutaneous; Interferon-gamma; Interleukins; Kaplan-Meiers Estimate; Kidney Neoplasms; Lymph Nodes; Lymphocyte Count; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Neoplasms, Experimental; Time Factors; Treatment Outcome

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

U2 - 10.1097/CJI.0b013e3181c0c1cb

DO - 10.1097/CJI.0b013e3181c0c1cb

M3 - Journal article

C2 - 20445344

VL - 33

SP - 236

EP - 249

JO - Journal of Immunotherapy

JF - Journal of Immunotherapy

SN - 1524-9557

IS - 3

ER -