Positive immunological effects of cancer chemotherapeutics unveiled

Lesterhuis Joost

A group of researchers of the NCMLS and RUMC have recently published an article in The Journal of Clinical Investigation, describing a novel mechanism of action of platinum-based chemotherapeutics: disruption of tumor-induced immune suppression.

Using allogeneic and antigen-specific in vitro models, they found that when dendritic cells (major regulators of cellular immune responses) were activated in the presence of platinum-based chemotherapy, their T cell stimulatory capacity was strongly enhanced.

Expression of the immune-inhibitory molecule Programmed death receptor-ligand 2 (PD-L2) by dendritic cells was markedly reduced upon platinum exposure. The enhanced T cell stimulatory capacity by dendritic cells upon platinum exposure was abrogated when PD-L2 was inhibited by blocking antibodies. This was also observed when the regulator of PD-L2 expression, signal transducer and activator of transcription 6 (STAT6), was knocked down using siRNA. 

In addition, not only in dendritic cells, but also in tumor cells it was found that STAT6 is dephosphorylated by platinum compounds, leading to marked downregulation of PD-L2 and resulting in enhanced recognition by tumor-specific T cells. In line with these in vitro findings, Lesterhuis and colleagues observed in a retrospective study that patients with STAT6-expressing head and neck cancer displayed significantly enhanced recurrence-free survival upon treatment with cisplatin-based chemoradiation compared to patients with STAT6-negative tumors, demonstrating the clinical relevance of platinum-induced STAT6 modulation.

 

The PD-L2/STAT6 pathway is known as a major immunosuppressive network that paralyzes the immune system and builds an immune-evasive tumor microenvironment. These findings demonstrate that platinum compounds not only directly kill tumor cells but also enhance T cell stimulation by dendritic cells. At the same time tumor cells are also sensitized to lysis by cytotoxic T cells through inactivation of this pathway. This novel action of platinum compounds, which are part of the standard treatment of many cancer types, may extend their therapeutic application and provides a rationale for their use in combination with other immuno-stimulatory compounds to increase the clinical efficacy of cancer treatment.   

Authors: W. Joost Lesterhuis, Cornelis J.A. Punt, Stanleyson V. Hato, Dagmar Eleveld-Trancikova, Bastiaan J.H. Jansen, Stefan Nierkens, Gerty Schreibelt, Annemiek de Boer, Carla M.L. Van Herpen, Johannes H. Kaanders, Johan H.J.M. van Krieken, Gosse J. Adema, Carl G. Figdor, and I. Jolanda M. de Vries.


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