James Paget

Abstract Purpose: ATR inhibitors (ATRi) are in early phase clinical trials and have been shown to sensitize to chemotherapy and radiotherapy preclinically. Limited data have been published about the effect of these drugs on the tumor microenvironment. Experimental Design: We used an immunocompetent mouse model of HPV-driven malignancies to investigate the ATR inhibitor AZD6738 in combination with fractionated radiation (RT). Gene expression analysis and flow cytometry were performed posttherapy. Results: Significant radiosensitization to RT by ATRi was observed alongside a marked increase in immune cell infiltration. We identified increased numbers of CD3+ and NK cells, but most of this infiltrate was composed of myeloid cells. ATRi plus radiation produced a gene expression signature matching a type I/II IFN response, with upregulation of genes playing a role in nucleic acid sensing. Increased MHC I levels were observed on tumor cells, with transcript-level data indicating increased antigen processing and presentation within the tumor. Significant modulation of cytokine gene expression (particularly CCL2, CCL5, and CXCL10) was found in vivo, with in vitro data indicating CCL3, CCL5, and CXCL10 are produced from tumor cells after ATRi + RT. Conclusions: We show that DNA damage by ATRi and RT leads to an IFN response through activation of nucleic acid–sensing pathways. This triggers increased antigen presentation and innate immune cell infiltration. Further understanding of the effect of this combination on the immune response may allow modulation of these effects to maximize tumor control through antitumor immunity.

I SHOULD not have offered to the Royal Medical and Chirurgical Society a mere collection of cases such as this paper contains, if it were not for the hope that they may help to clearly indicate the chief characters of the disease to which I venture to give the name of osteitis deformans, and which, so far as I know, was first described in the paper published in the 60th volume of the Society's 'Transactions."Since that time, about five years ago, I After the publication of the paper I found that the name ostitis deformans had been given by Prof. Czerny, of Freiburg, to a disease described by him in the ' Wiener medizinische Wochenschrift,' September 27th, 1873.It is mainly, as he says, " Eine lokale Malacie des Unterschenkels," a rather acute inflammation of the lower part of the tibia and fibula, inducing softening and angular bending, and then followed by hardening.A specimen of the only instance of this disease that I have seen has lately been presented to the Museum of the College of Surgeons by Dr. Butt, of Hereford.Like all Prof. Czerny's cases it occurred in a young man.It may be well to add also that the sternum, a clavicle, and a rib of thp man, whose case by Saucerotte is referred to in my last paper, are in the Mus6e Dupuytren.They were obtained by Saucerotte many years after his account of the case was published.The description of them in the ' DapdIf tren Catalogue,' vol.ii, p. 148, leaves it very doubtful whether the disease was osteitis deformans.15 VOL.LXV.