Accumulating evidence suggests that exogenous cellular stress induces PD-L1 upregulation in cancer. A DNA double-strand break (DSB) is the most critical type of genotoxic stress, but the involvement of DSB repair in PD-L1 expression has not been investigated. Here we show that PD-L1 expression in cancer cells is upregulated in response to DSBs. This upregulation requires ATM/ATR/Chk1 kinases. Using an siRNA library targeting DSB repair genes, we discover that BRCA2 depletion enhances Chk1-dependent PD-L1 upregulation after X-rays or PARP inhibition. In addition, we show that Ku70/80 depletion substantially enhances PD-L1 upregulation after X-rays. The upregulation by Ku80 depletion requires Chk1 activation following DNA end-resection by Exonuclease 1. DSBs activate STAT1 and STAT3 signalling, and IRF1 is required for DSB-dependent PD-L1 upregulation. Thus, our findings reveal the involvement of DSB repair in PD-L1 expression and provide mechanistic insight into how PD-L1 expression is regulated after DSBs.

The biological effectiveness of proton beams relative to photon beams in radiation therapy has been taken to be 1.1 throughout the history of proton therapy. While potentially appropriate as an average value, actual relative biological effectiveness (RBE) values may differ. This Task Group report outlines the basic concepts of RBE as well as the biophysical interpretation and mathematical concepts. The current knowledge on RBE variations is reviewed and discussed in the context of the current clinical use of RBE and the clinical relevance of RBE variations (with respect to physical as well as biological parameters). The following task group aims were designed to guide the current clinical practice: Assess whether the current clinical practice of using a constant RBE for protons should be revised or maintained. Identifying sites and treatment strategies where variable RBE might be utilized for a clinical benefit. Assess the potential clinical consequences of delivering biologically weighted proton doses based on variable RBE and/or LET models implemented in treatment planning systems. Recommend experiments needed to improve our current understanding of the relationships among in vitro, in vivo, and clinical RBE, and the research required to develop models. Develop recommendations to minimize the effects of uncertainties associated with proton RBE for well‐defined tumor types and critical structures.