CD73 Blockade Promotes Dendritic Cell Infiltration of Irradiated Tumors and Tumor Rejection
Authors: Silvia C Formenti
Sylvia Gruber
Claire Lhuillier
Xi K Zhou
Qiuying Chen
Steven S Gross
Erik Wennerberg
Sheila Spada
Sandra Demaria
Nils-Petter Rudqvist
Fengli Zhang
Journal: Cancer Immunology Research (2020)
Discipline: CLINICAL MEDICINE
Keywords: focal radiotherapy; tumor-specific CD8+ T cells; immunotherapy; Batf3-dependent cDC1 cells; IFN type I
Affiliations: Department of Radiation Oncology, Weill Cornell Medicine, New York, New York., Department of Pharmacology, Weill Cornell Medicine, New York, New York., Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, New York., Department of Radiation Oncology, Weill Cornell Medicine, New York, New York. ., Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York.

Abstract:  The ability of focal radiotherapy to promote priming of tumor-specific CD8+ T cells and increase responses to immunotherapy is dependent on infiltration of the tumor by Batf3-dependent conventional dendritic cell type 1 (cDC1) cells. Such infiltration is driven by radiotherapy-induced IFN type I (IFN-I). Other signals may also modulate cDC1 infiltration of irradiated tumors. Here we found increased expression of adenosine-generating enzymes CD38 and CD73 in irradiated mouse and human breast cancer cells and increased adenosine in mouse tumors following radiotherapy. CD73 blockade alone had no effect. CD73 blockade with radiotherapy restored radiotherapy-induced cDC1 infiltration of tumors in settings where radiotherapy induction of IFN-I was suboptimal. In the absence of radiotherapy-induced IFN-I, blockade of CD73 was required for rejection of the irradiated tumor and for systemic tumor control (abscopal effect) in the context of cytotoxic T-lymphocyte-associated protein 4 blockade. These results suggest that CD73 may be a radiation-induced checkpoint, and that CD73 blockade in combination with radiotherapy and immune checkpoint blockade might improve patient response to therapy. 

Retracted: No

PubPeer comments:
 By reading the sentence  However, CD73 blockade restored the ability of the combination of 8 Gyu00d73 radiotherapy and CTLA-4-blockade to induce abscopal responses and extend survival of mice with TSAshcGAS primary tumors (Fig. 7B-C) this peer expected a statistical comparison between TSAshNS and TSAshCGAS tumors under each of the treatments, which is not provided. Perhaps the authors can comment and provide such comparison? It would be useful as some treatments have responses that are more similar than expected from a cGAS-competent versus cGAS-incompetent background (especially 8 Gyx3 plus CTLA-blockade, which the same team previously demonstrated to mediate ascopal response only in the presence of cgAS ![file] , 
 #1 Thank you for reading with interest our paper. Concerning your question, the p-values are shown in the panel C where the survival is shown. Survival reflects the long-term control of both, irradiated and abscopal tumors, and is the most accurate measure of the effectiveness of the treatment. In the sentence you quote we in fact say  to induce abscopal responses and extend survival of mice with TSAshcGAS primary tumors . We hope that this answers your question. Please, let us know if you have additional queries. Thank you Erik Wennerberg and Sandra Demaria ,