Mutational Features and Tumor Microenvironment Alterations in High-Grade Appendiceal Cancers Treated With Iterative...

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• High-grade appendiceal adenocarcinomas (HGAA) with peritoneal metastases (PMs) have a poor prognosis.
• Hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment option for unresectable HGAA-PM.
• The immunogenomic impact of HIPEC on HGAA-PM is not well understood.

Purpose of the Study:

• To explore the immunogenomic changes in HGAA-PM after HIPEC.
• To identify mutational signatures and immune cell populations associated with HIPEC treatment outcomes.

Main Methods:

• Whole-exome sequencing, RNA sequencing, and immunoprofiling of 79 metastatic peritoneal tumor deposits from HGAA patients.
• Analysis of tumor biopsies before and after HIPEC to detect mutational signatures and immune populations.

Main Results:

• Fifteen patients with HGAA-PM were analyzed.
• Commonly mutated genes included MUC16, MUC3A, MUC5AC, and TTN.
• Mutational signatures (SBS29, DBS11) were prevalent.
• Higher PD-L1 coexpression on CD8+ T cells correlated with improved progression-free survival (PFS) both intratumorally and at the margin (P=.019, P=.025).

Conclusions:

• HIPEC induces specific mutational signatures in HGAA-PM.
• Elevated PD-L1+ cytotoxic T-cell populations post-HIPEC are associated with better PFS.
• These findings offer insights for prognostication in HGAA-PM patients treated with HIPEC.