UVB-irradiated apoptotic cells induce accelerated growth of co-implanted viable tumor cells in immune competent mice

Abstract

The presence of a solid tumor is the result of a complex balance between rejection, tolerance and regeneration in which the interactions of tumor cells with cells of the host immune system contribute strongly to the final outcome. Here we report on a model where lethally UVB-irradiated cells cause accelerated growth of viable tumor cells in vitro and in allogeneic immune competent mice. UVB-irradiated tumor cells alone did not form tumors and failed to induce tolerance for a second challenge with the same allogeneic tumor. Our data show an important role for dying cells in promoting accelerated tumor cell growth of a small number of viable tumor cells in a large inoculum of UVB-irradiated tumor cells. This occurs when viable and dying/dead tumor cells are in close proximity, suggesting that mobile factors contribute to growth promotion. The anti-inflammatory and growth promoting properties of apoptotic cells are based on several independent effects. UVB-irradiated apoptotic cells directly release a growth promoting activity and clearance by macrophages of apoptotic cells is accompanied by the secretion of IL10, TGFß, and PGE2. Growth promotion is even observed with dying heterologous cells implying a conserved mechanism. Future experiments should focus on the effects of dying tumor cells generated in vivo on the outgrowth of surviving tumor cells which is prone to have implications for cancer therapy.

Keywords::

• Apoptosis
• UVB-irradiation
• tumor growth
• melanoma
• clearance

Declaration of interests : This project was supported by the German Research Foundation (collaborative research center 643, GA 1507/1-1 and DFG -Graduiertenkolleg 1660: Key signals of the adaptive immune response), by the Emerging Fields Initiative (EFI) of the FAU Erlangen-Nuremberg, by the IZKF of the University Hospital Erlangen, by the European Commission, the German Federal Ministry of Education and Research (BMBF; m4 Cluster, 01EX1021R), and the K. und R. Wucherpfennig-Stiftung. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.