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Abstract

Preclinical and clinical evidence indicate that the proimmune effects of radiotherapy can be synergistically augmented with immunostimulatory mAbs to act both on irradiated tumor lesions and on distant, nonirradiated tumor sites. The combination of radiotherapy with immunostimulatory anti-PD1 and anti-CD137 mAbs was conducive to favorable effects on distant nonirradiated tumor lesions as observed in transplanted MC38 (colorectal cancer), B16OVA (melanoma), and 4T1 (breast cancer) models. The therapeutic activity was crucially performed by CD8 T cells, as found in selective depletion experiments. Moreover, the integrities of BATF-3-dependent dendritic cells specialized in crosspresentation/crosspriming of antigens to CD8+ T cells and of the type I IFN system were absolute requirements for the antitumor effects to occur. The irradiation regimen induced immune infiltrate changes in the irradiated and nonirradiated lesions featured by reductions in the total content of effector T cells, Tregs, and myeloid-derived suppressor cells, while effector T cells expressed more intracellular IFNγ in both the irradiated and contralateral tumors. Importantly, 48 hours after irradiation, CD8+ TILs showed brighter expression of CD137 and PD1, thereby displaying more target molecules for the corresponding mAbs. Likewise, PD1 and CD137 were induced on tumor-infiltrating lymphocytes from surgically excised human carcinomas that were irradiated ex vivo These mechanisms involving crosspriming and CD8 T cells advocate clinical development of immunotherapy combinations with anti-PD1 plus anti-CD137 mAbs that can be synergistically accompanied by radiotherapy strategies, even if the disease is left outside the field of irradiation. 

Author information​

Rodriguez-Ruiz ME1, Rodriguez I2, Garasa S2, Barbes B2, Solorzano JL3, Perez-Gracia JL3, Labiano S2, Sanmamed MF4, Azpilikueta A2, Bolaños E2, Sanchez-Paulete AR2, Aznar MA2, Rouzaut A2, Schalper KA5, Jure-Kunkel M6, Melero I7.

1Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain. University Clinic, University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain.

2Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain.

3University Clinic, University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain.

4Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain. Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut.

5Department of Pathology, Yale School of Medicine, New Haven, Connecticut. Department of Medicine (Medical Oncology), Yale School of Medicine, New Haven, Connecticut.

6Bristol-Myers Squibb, Lawrenceville, New Jersey. imelero@unav.es mrruiz@unav.es.

7Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain. University Clinic, University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Pamplona, Spain. imelero@unav.es mrruiz@unav.es. 

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