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

ABSTRACT: We have previously shown that within tumors, recombinant interleukin-2 (rIL-2, Aldesleukin) consistently activates tumor-associated macrophages and up-regulates interferon stimulated genes (ISGs) 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 (PBMCs) and within melanoma metastases by serially comparing pre- to post-treatment samples in 13 patients. We 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 to non-responding ones. As previously described, the effects of rIL-2 were dramatic within PBMC, while effects within the tumor microenvironment were lesion-specific and limited. However, distinct signatures specific to response could be observed in responding lesions pre-treatment 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 underlying a common pathways leading to rejection. Moreover, the signatures observed in pre-treatment 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. This is the first prospectively collected insight on global transcriptional events occurring during high-dose rIL-2 therapy in melanoma metastases responding to treatment. Evaluated transcriptional alterations induced by rIL-2 in peripheral blood mononuclear cells (PBMCs) (n=34) and within melanoma metastases (n=30) by serially comparing pre- (n=34) to post-treatment (n=30) samples in 13 patients.

ORGANISM(S): Homo sapiens

SUBMITTER: Marincola Francesco 

PROVIDER: S-ECPF-GEOD-32611 | biostudies-other |

REPOSITORIES: biostudies-other