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Mutational Features and Tumor Microenvironment Alterations in High-Grade Appendiceal Cancers treated with iterative Hyperthermic Intraperitoneal Chemotherapy (HIPEC)
*David G. Su M.D.1, *Ankit Dhiman 2, *Varun V. Bansal 1, *Yuanyuan Zha 3, *Ardaman Shergill 4, *Blasé Polite 4, *Lindsay Alpert 3, Kiran Turaga MD, MPH, FACS1, *Oliver S. Eng 5
1General Surgery, Yale New Haven Hospital, Hamden, CT; 2Surgery, Medical College of Georgia, Atlanta, GA; 3Pathology, University of Chicago Medical Center, Chicago, IL; 4Hematology/Oncology, University of Chicago Medical Center, Chicago, IL; 5Surgery, University of California, Irvine, Irvine, CA

PURPOSE
High grade appendiceal adenocarcinomas (HGAA) with peritoneal metastases (PMs) are associated with poor survival. Hyperthermic intraperitoneal chemotherapy (HIPEC) is a novel treatment approach for unresectable HGAA-PM. However, its influence on immunogenomic profiles has not yet been fully explored.

METHODS
We obtained 79 samples of metastatic peritoneal tumor deposits from patients diagnosed with HGAA and performed whole-exome sequencing, RNA sequencing, and immunoprofiling before and after HIPEC. Tumor biopsies were subjected to immunogenomic profiling to detect mutational signatures and immune populations associated with oncologic outcomes.

RESULTS
Fifteen patients with HGAA-PMs were included in the study. The median progression-free survival (PFS) was 6.7 months (2.7 to 25.3), and the median OS was 11.4 months (4.7 to 42). Mucin-associated genes (MUC16, MUC17, MUC3A) and titin (TTN) had the highest mutation frequencies. Mutational signatures such as single-base substitution (SBS)29 and double-base substitution (DBS)11 were present in >50% of single-base and double-base mutations. Higher programmed cell death protein-ligand 1 (PD-L1) co-expression on CD8+ T cells demonstrated a higher PFS both intratumorally (p = 0.019) and at the margin (p = 0.025).

CONCLUSION
HIPEC-associated immune populations and mutational signatures were identified in HGAA-PM, offering valuable insights for prognostication in the context of HIPEC treatment.

Figure 1. Study design. HIPEC, hyperthermic intraperitoneal chemotherapy; IF, immunofluorescence; TME, tumor microenvironment. “X” denotes any time point (A-D). Created with Biorender.

A. Summary of the mutational landscape (n = 15 patients) in pre- and post-HIPEC tumors. Oncoplot of the top 20 mutated genes that contain any variant in the highest percentage of the patients displayed. Each column denotes a sample and each row denotes a gene or pathway. TMB, tumor mutation burden. B. HIPEC-associated mutational signatures. Mutational distribution for four Single Base Substitution (SBS) signatures associated with HIPEC treatments, using the COSMIC signature database (extracted from SigProfiler).

HIPEC-associated changes of the tumor microenvironment assessed by multiplex immunofluorescence estimations in pre- and post-HIPEC tumors. (A) Representative immunofluorescence images demonstrating increased tumor-infiltrating lymphocytes after HIPEC. Scale bars: 50 µm (white); 10 µm (red). (B) Cell densities of CD8+ T-cells and CD4+ T-cells at the invasive margin or intratumorally do not change with HIPEC treatments. (C) PD-L1 expression in CD8+ T cells at the tumor and invasive margin after multiple iterations of HIPEC. (D) Kaplan-Meier curves of PFS in patients with high (red) versus low (blue) changes in PD-L1 expression changes in CD8+ TILs, dichotomized on the median PD-L1 thresholds. HIPEC, hyperthermic intraperitoneal chemotherapy; NS, non-significant; PD-1, programmed cell death protein 1; PFS, progression free survival; TIL, tumor infiltrating lymphocyte.


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