Hugang Feng1, Karen A. Lane1, Theodoros I. Roumeliotis1, Penny A. Jeggo2, Navita Somaiah1,3, Jyoti S. Choudhary1 and Jessica A. Downs1 1The Institute of Cancer Research, London SW3 6JB, United Kingdom; 2Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, United Kingdom; 3The Royal Marsden National Health Service Foundation Trust, London SM2 5PT, United Kingdom Corresponding author: jessica.downsicr.ac.uk Abstract

The PBRM1 subunit of the PBAF (SWI/SNF) chromatin remodeling complex is mutated in ∼40% of clear cell renal cancers. PBRM1 loss has been implicated in responses to immunotherapy in renal cancer, but the mechanism is unclear. DNA damage-induced inflammatory signaling is an important factor determining immunotherapy response. This response is kept in check by the G2/M checkpoint, which prevents progression through mitosis with unrepaired damage. We found that in the absence of PBRM1, p53-dependent p21 up-regulation is delayed after DNA damage, leading to defective transcriptional repression by the DREAM complex and premature entry into mitosis. Consequently, DNA damage-induced inflammatory signaling pathways are activated by cytosolic DNA. Notably, p53 is infrequently mutated in renal cancer, so PBRM1 mutational status is critical to G2/M checkpoint maintenance. Moreover, we found that the ability of PBRM1 deficiency to predict response to immunotherapy correlates with expression of the cytosolic DNA-sensing pathway in clinical samples. These findings have implications for therapeutic responses in renal cancer.

Received December 7, 2021. Accepted July 13, 2022.