Mechanisms underlying curative control of irradiated and non-irradiated tumors by radio-immunotherapy
P Kroon1*, V Iglesias1*, E Frijlink1, M van Buuren1, M Toebes1, C Linnemann1, T Schumacher1, M Verheij2, J Borst1# and I Verbrugge1#
1Division of Immunology, 2Department of Radiotherapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands
*co-first, #co-senior authorship
Radiotherapy combined with T-cell modulating immunotherapy (‘radio-immunotherapy’) is a promising new cancer therapy. Radio-immunotherapy can potentially control non-irradiated tumors outside the radiation field, but has not yet resulted in improved overall survival in randomized clinical trials.
In the transplantable AT-3 mouse breast cancer model, radio-immunotherapy with -CD137 and -PD-1 mAbs eliminates irradiated tumors in a CD8+ T-cell-dependent manner. However, non-irradiated tumors are not eliminated in the same experimental setting, indicating lack of systemic, immune activating synergy.
Here, we investigated the underlying mechanisms determining synergy of our radio-immunotherapy approach on the irradiated tumor, and aimed to identify the mechanisms impeding a systemic combined effect against non-irradiated AT-3 tumors.
Blocking T cell egress from lymphoid organs with FTY720, almost completely abrogated curative radio-immunotherapy responses, indicating that enhanced T cell priming is required to mediate eradication of irradiated tumors. However, enhanced T cell priming was not sufficient to mediate eradication of non-irradiated tumors, which we demonstrated using a DNA tattoo vaccine that raised a large tumor-specific CTL response to an identified tumor antigen with moderate MHC I affinity. This vaccine delayed but did not eradicate outgrowth of non-irradiated tumors.
Collectively, our data suggest that –for tumors expressing weakly immunogenic epitopes– combining radio-immunotherapy with strategies that enhance T cell priming and modulate the tumor micro-environment beyond PD-1 signalling will be critical to achieve control of non-irradiated tumors and ultimately improve overall survival in randomized clinical radio-immunotherapy trials.
Funding: Dutch Cancer Society to I Verbrugge (NKI2013-5951)