Olivia Smith

DNA mismatch repair deficiency (MMRd) is associated with a high tumor mutational burden (TMB) and sensitivity to immune checkpoint blockade (ICB) therapy. Nevertheless, most MMRd tumors do not durably respond to ICB and critical questions remain about immunosurveillance and TMB in these tumors. In the present study, we developed autochthonous mouse models of MMRd lung and colon cancer. Surprisingly, these models did not display increased T cell infiltration or ICB response, which we showed to be the result of substantial intratumor heterogeneity of mutations. Furthermore, we found that immunosurveillance shapes the clonal architecture but not the overall burden of neoantigens, and T cell responses against subclonal neoantigens are blunted. Finally, we showed that clonal, but not subclonal, neoantigen burden predicts ICB response in clinical trials of MMRd gastric and colorectal cancer. These results provide important context for understanding immune evasion in cancers with a high TMB and have major implications for therapies aimed at increasing TMB.

INTRODUCTION: The present study aims to evaluate the short-term and long-term outcomes of patients undergoing restorative proctocolectomy (RPC) for Crohn's disease (CD) and Indeterminate colitis (IC) and to identify factors associated with adverse outcomes. METHODS: A descriptive study of 52 patients with CD or IC from a total of 1652 patients undergoing primary or salvage RPC in a single tertiary referral centre between 1978 and 2003. Primary outcomes were ileal pouch failure (excision or indefinite diversion), adverse events and functional outcomes (bowel frequency, urgency and continence). RESULTS: Patients with IC or IC favouring ulcerative colitis (Group 1, n = 26) had a pouch failure rate of 11.5%vs 57.5% for patients with CD or IC favouring CD (Group 2, n = 26). Pouch salvage surgery was undertaken in 15 patients with a 13.3% failure rate. Patients in Group 2 were 2.6 times more likely (95% CI: 0.96-7. No significant differences were evident between CD and IC patients with regards to pelvic sepsis (19.2%vs 15.4%), anastomotic stricture (23.1%vs 21.7%), small bowel obstruction (26.9%vs 26.9%) or pouchitis (15.4%vs 11.5%). The 24-h bowel frequency (7.5 vs 8), faecal urgency, daytime or night time incontinence were similar between patients with CD or IC..17) to develop a pouch-related fistula than patients in Group 1. DISCUSSION: Crohn's disease and to a great extent indeterminate colitis favouring CD were both associated with high failure rates and postoperative pouch-related fistula rates. Despite these problems, functional outcomes for patients with CD or IC were similar. Patients with IC should remain candidates for RPC but careful pre-operative assessment is advised to exclude clinical signs favouring the diagnosis of CD. The complications associated with failure are extensive and the option of reconstructive surgery in patients with CD should be questioned.