Intratumoral Interleukin-21 Increases Antitumor Immunity, Tumor-infiltrating CD8(+) T-cell Density and Activity, and Enlarges Draining Lymph Nodes

TY - JOUR

T1 - Intratumoral Interleukin-21 Increases Antitumor Immunity, Tumor-infiltrating CD8(+) T-cell Density and Activity, and Enlarges Draining Lymph Nodes

AU - Sondergaard, H.

AU - Galsgaard, E.D.

AU - Bartholomaeussen, M.

AU - Straten, P.T.

AU - Odum, N.

AU - Skak, K.

PY - 2010/4

Y1 - 2010/4

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-cellmediated 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 CD4 +CD25 - T cells, but not CD4 +CD25 + FoxP3 +T cells. Furthermore, IT administration of IL-21 increased degranulation, and expression of interferon-y and granzyme B in tumorinfiltrating 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-cellmediated 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 CD4 +CD25 - T cells, but not CD4 +CD25 + FoxP3 +T cells. Furthermore, IT administration of IL-21 increased degranulation, and expression of interferon-y and granzyme B in tumorinfiltrating 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.

M3 - Journal article

SN - 1524-9557

VL - 33

SP - 236

EP - 249

JO - Journal of Immunotherapy

JF - Journal of Immunotherapy

IS - 3

ER -