Molecular insights on the peripheral and intratumoral effects of systemic high-dose rIL-2 (aldesleukin) administration for the treatment of metastatic melanoma

Geoffrey R. Weiss, William W. Grosh, Kimberly A. Chianese-Bullock, Yingdong Zhao, Hui Liu, Craig L. Slingluff, Francesco M. Marincola, Ena Wang

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)7440-7450
Number of pages11
JournalClinical Cancer Research
Volume17
Issue number23
DOIs
Publication statusPublished - 1 Dec 2011
Externally publishedYes

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Melanoma
Neoplasms
Neoplasm Metastasis
Tumor Microenvironment
Therapeutics
Interleukin-2
Blood Cells
Research Design
Theoretical Models
Up-Regulation
Macrophages
T-Lymphocytes
Gene Expression
aldesleukin
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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. / Weiss, Geoffrey R.; Grosh, William W.; Chianese-Bullock, Kimberly A.; Zhao, Yingdong; Liu, Hui; Slingluff, Craig L.; Marincola, Francesco M.; Wang, Ena.

In: Clinical Cancer Research, Vol. 17, No. 23, 01.12.2011, p. 7440-7450.

Research output: Contribution to journalArticle

Weiss, Geoffrey R. ; Grosh, William W. ; Chianese-Bullock, Kimberly A. ; Zhao, Yingdong ; Liu, Hui ; Slingluff, Craig L. ; Marincola, Francesco M. ; Wang, Ena. / Molecular insights on the peripheral and intratumoral effects of systemic high-dose rIL-2 (aldesleukin) administration for the treatment of metastatic melanoma. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 23. pp. 7440-7450.
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