Ras oncoproteins transfer from melanoma cells to T cells and modulate their effector functions

Helly Vernitsky, Oded Rechavi, Nir Rainy, Michal J. Besser, Meital Nagar, Jacob Schachter, Yaniv Lerenthal, Marcelo Ehrlich, Yoel Kloog, Itamar Goldstein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Lymphocytes establish dynamic cell-cell interactions with the cells they scan. Previous studies show that upon cell contact, various membrane-associated proteins, such as Ras-family proteins, transfer from B to T and NK lymphocytes. Mutations in RAS genes that encode constitutively active, GTP-bound, oncoproteins are rather common in human cancers; for instance, melanoma. Cancer immunoediting has been postulated to contribute to the elimination of malignant melanoma. Thus, we asked whether Ras oncoproteins can transfer from melanoma to T cells, including tumor-infiltrating lymphocytes (TILs), and subsequently induce functional effects in the adopting T cells. To explore this issue, we genetically engineered an HLA-A2+ melanoma cell line, MEL526, to express GFP or GFP-tagged H-Ras mutants stably. In this study, we show by an in vitro coculture system that GFP-tagged H-Ras, but not GFP, transfers from MEL526 to T cells and localizes to the inner aspect of their plasma membrane. This cell-contact-dependent process was increased by TCR stimulation and did not require strict Ag specificity. Importantly, we found a positive correlation between the levels of the acquired constitutively active H-RasG12V and ERK1/2 phosphorylation within the adopting TILs. We also show a significant increase in IFN-γ production and cytotoxic activity in TILs that acquired HRasG12V compared to TILs that acquired a different H-Ras mutant. In conclusion, our findings demonstrate a hitherto unknown phenomenon of intercellular transfer of Ras oncoproteins from melanoma to TILs that consequently augments their effector functions.

Original languageEnglish
Pages (from-to)4361-4370
Number of pages10
JournalJournal of Immunology
Volume189
Issue number9
DOIs
StatePublished - 1 Nov 2012

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