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Molecular Insights on the Peripheral and Intratumoral Effects of Systemic High-Dose rIL-2 (Aldesleukin) Administration for the Treatment of Metastatic Melanoma
- Source :
- Clinical Cancer Research. 17:7440-7450
- Publication Year :
- 2011
- Publisher :
- American Association for Cancer Research (AACR), 2011.
-
Abstract
- Purpose: We have previously shown that within tumors, recombinant interleukin-2 (rIL-2, aldesleukin) consistently activates tumor-associated macrophages and upregulates IFN-stimulated genes while inducing minimal migration, activation, or proliferation of T cells. These effects are independent of tumor response to treatment. Here, we prospectively evaluated transcriptional alterations induced by rIL-2 in peripheral blood mononuclear cells (PBMC) and within melanoma metastases. Experimental Design: We evaluated gene expression changes by serially comparing pre- to posttreatment samples in 13 patients and also compared transcriptional differences among lesions displaying different responsiveness to therapy, focusing on 2 lesions decreasing in size and 2 remaining stable (responding lesions) compared with nonresponding ones. Results: As previously described, the effects of rIL-2 were dramatic within PBMCs, whereas effects within the tumor microenvironment were lesion specific and limited. However, distinct signatures specific to response could be observed in responding lesions pretreatment that were amplified following rIL-2 administration. These signatures match the functional profile observed in other human or experimental models in which immune-mediated tissue-specific destruction (TSD) occurs, underscoring common pathways leading to rejection. Moreover, the signatures observed in pretreatment lesions were qualitatively similar to those associated with TSD, underlining a determinism to immune responsiveness that depends upon the genetic background of the host or the intrinsic genetic makeup of individual tumors. Conclusions: This is the first prospectively collected insight on global transcriptional events occurring during high-dose rIL-2 therapy in melanoma metastases responding to treatment. Clin Cancer Res; 17(23); 7440–50. ©2011 AACR.
- Subjects :
- Adult
Male
Interleukin 2
Cancer Research
Antineoplastic Agents
Biology
Peripheral blood mononuclear cell
Article
Immune system
Aldesleukin
Interferon
Tumor Microenvironment
medicine
Humans
Neoplasm Metastasis
Melanoma
Aged
Oligonucleotide Array Sequence Analysis
Regulation of gene expression
Tumor microenvironment
Interleukin-17
Middle Aged
medicine.disease
Recombinant Proteins
Gene Expression Regulation, Neoplastic
Oncology
Immunology
Leukocytes, Mononuclear
Interleukin-2
Female
medicine.drug
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....9f8975604e51ab9ddfbc2e71d5f6f9b2