Gene Therapy: Ccl21 (Slc) Inhibits Primary Prostate Tumor Growth and Metastases

Abstract

TRAMPC2 (transgenic adenocarinoma of mouse prostate) tumors are heavily infiltrated with myeloid but not lymphoid (T and B) cells that may reflect the accumulation of immature dendritic cells (DCs) in TRAMPC2 tumors. Secondary lymphoid tissue chemokine (CCL21, SLC) is chemotactic for T cells and DCs and may serve as co‐localization signal for these cells during early phases of the cellular immune response to prostate tumors. We proposed in this study that modification of tumor microenvironment (TME) by expression of CCL21 in TRAMP tumor would induce infiltration of DCs and T cells and minimizes the myeloid cell infiltrate that appears to be responsible for disruption of T cell signaling complex. We generated TRAMPC2 cell lines with regulated expression of CCL21 using the tetracycline responsive promoter, so that we could activate the transgene at selected times during tumor progression (tet on system). Orthotopic tumor volumes were smaller in tetracycline treated mice and these mice lived longer than control mice. Lymph node (LN) metastasis was detected in all 3 control mice (1 found dead) whereas only 2 out of 4 treated mice had LN metastasis. 2 out of 3 untreated mice but only 1 out of 4 treated mice had lung metastasis. Our data indicates that expression of CCL21 in the prostate TME inhibits tumor growth and prevents metastasis and may represent a novel approach to modulate anti‐tumor immunity and tumor growth.