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Flt3-ligand induces transient tumor regression in an ectopic treatment model of major histocompatibility
R P Ciavarra1, K D Somers, R R Brown
1Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk 23501, USA. rpc@borg.evms.edu
Abstract:
We assessed the in vivo efficacy of Flt3-ligand (Flt3-L) treatment in C57BL/6 mice bearing a well-established MHC class I-negative prostate carcinoma TRAMP-C1. Flt3-L immunotherapy was initiated approximately 30 days after tumor inoculation, a time when > or =80% of the mice had palpable TRAMP-C1 tumors. Treatment with Flt3-L at 10 microg/day for 21 consecutive days suppressed TRAMP-C1 tumor growth and induced tumor stabilization (P = 0.0337). Enhanced tumor regression was demonstrated at a higher dose of 30 microg/day (P < 0.0001). Tumors excised from mice treated with Flt3-L were smaller than carrier-treated controls and contained a more pronounced mixed inflammatory cell infiltrate primarily composed of mphi. In regressor nice, tumors reappeared at the site of injection when Flt3-L therapy was terminated. When the experiment was repeated with MHC class I-positive TRAMP-C1 cells, tumor stabilization and/or regression was again observed after treatment (P < 0.0001); however, once again, tumors reappeared after the termination of therapy despite an extended treatment schedule (35 days). MHC class I-negative variants were present in tumors isolated from carrier- and Flt3-L-treated mice, and this phenotype could be reversed by IFN-gamma treatment in vitro. Thus, Flt3-L treatment of mice with preexisting transplantable prostate tumors results in tumor regression that is dose-dependent and accompanied by a pronounced mixed-cell inflammatory tumor infiltrate. However, disease relapse was invariably observed after the termination of therapy, which suggests that Flt3-L treatment of advanced MHC- prostate cancers will require adjuvant modalities to achieve a durable response.
Insights
Flt3-ligand (Flt3-L) immunotherapy suppressed prostate tumor growth in mice, with higher doses enhancing regression. However, tumors recurred after treatment cessation, indicating Flt3-L may need adjuvant therapies for lasting prostate cancer responses.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Prostate carcinoma is a significant health concern.
- Flt3-ligand (Flt3-L) is a cytokine that promotes dendritic cell and myeloid progenitor development.
- The efficacy of Flt3-L immunotherapy in established prostate tumors, particularly those with varying MHC class I expression, requires further investigation.
Purpose of the Study:
- To evaluate the in vivo efficacy of Flt3-ligand (Flt3-L) immunotherapy against established TRAMP-C1 prostate carcinoma in mice.
- To assess the dose-dependent effects of Flt3-L on tumor growth, regression, and inflammatory infiltrate.
- To investigate the role of MHC class I expression and the potential for tumor relapse after Flt3-L treatment.
Main Methods:
- C57BL/6 mice were inoculated with either MHC class I-negative or MHC class I-positive TRAMP-C1 prostate carcinoma cells.
- Flt3-L immunotherapy was administered at doses of 10 microg/day or 30 microg/day for 21-35 consecutive days, starting when tumors were palpable.
- Tumor growth, regression, inflammatory cell infiltration (primarily macrophages), MHC class I expression, and relapse after treatment cessation were analyzed.
Main Results:
- Flt3-L treatment suppressed tumor growth and induced stabilization at 10 microg/day (P = 0.0337) and significant regression at 30 microg/day (P < 0.0001) in MHC class I-negative tumors.
- Tumors from Flt3-L treated mice showed reduced size and increased inflammatory infiltrate, predominantly macrophages.
- Tumor relapse was observed in both MHC class I-negative and positive models after Flt3-L therapy termination, with MHC class I-negative variants emerging.
- IFN-gamma treatment in vitro could reverse the MHC class I-negative phenotype.
Conclusions:
- Flt3-L immunotherapy demonstrates dose-dependent efficacy in regressing established prostate tumors in mice, accompanied by an inflammatory infiltrate.
- The emergence of MHC class I-negative variants and subsequent tumor relapse after Flt3-L cessation highlight the need for combination strategies.
- Adjuvant therapies are likely necessary to achieve durable responses in advanced prostate cancers treated with Flt3-L.
