Rapid release of cytoplasmic IL‐15 from tumor‐associated macrophages is an initial and critical event in IL‐12‐initiated tumor regression

This study reveals that the IL‐15 rapidly released into serum upon IL‐12 injection into tumor‐bearing mice is critical for the subsequent leukocytic infiltration of the tumor and tumor‐bearing tissue. The increase in serum IL‐15 occurs within 2 h after IL‐12 injection concomitantly with a decrease in cytoplasmic IL‐15 in tumor‐associated M? (TAM). Injection of anti‐IL‐15 one hour prior to IL‐12 abrogates subsequent leukocytic infiltration into the tumor and prevents the IL‐12‐induced reduction of primary tumor mass and the clearance of metastases. Administration of anti‐IL‐15 18 h after IL‐12 did not have a detectable impact on IL‐12‐induced leukocytic infiltration of the tumor. Deletion of NK cells had no impact on the IL‐12‐induced change in the functional phenotype of TAM or on the subsequent initiation of leukocytic infiltration of the tumor. In concert with our previous studies demonstrating that IL‐12 reduces tumor‐supportive activities of TAM, the current study supports the hypothesis that functional re‐programming of TAM not only undermines M? support for tumor growth but also contributes to a critical step in the initiation of anti‐tumor immune responses. In this context, the functional plasticity and pro‐immunogenic potential of TAM may constitute a significant and unappreciated target in existing cytokine therapies.