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 Mphi (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 Mphi 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.
Watkins
Stephanie K
SK
Department of Microbiology, and James Graham Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40292, USA.
Li
Bing
B
Richardson
Katharine S
KS
Head
Kimberly
K
Egilmez
Nejat K
NK
Zeng
Qun
Q
Suttles
Jill
J
Stout
Robert D
RD
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018664:Interleukin-12 / Q000008:administration & dosage / Q000494:pharmacology*; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics; D047368:Tumor Burden / Q000187:drug effects
D000906:Antibodies; D016207:Cytokines; D019409:Interleukin-15; D016212:Transforming Growth Factor beta; D018664:Interleukin-12