Abstract C013: Analysis of tumor immune microenvironment and clinical outcomes in undifferentiated pancreatic carcinomas with and without osteoclast-like giant cells
Authors: Mills Jamie N. , Gunchick Valerie , Shi Jiaqi , Udager Aaron , Frankel Timothy , Zalupski Mark M. , Sahai Vaibhav 
Published: January 2024

Abstract
Background: Undifferentiated carcinoma (UC) is a rare (&lt;1%) subtype of pancreatic cancer that was revised in 2010 per WHO classification as UC with or without osteoclast-like giant cells (OGC), affecting interpretation of prior literature comparing UC to pancreatic ductal adenocarcinomas (PDAC). Limited retrospective data suggest UC-OGC occurs at younger age with larger tumor size but the impact on prognosis is unclear, and there no data on the tumor immune microenvironment (TIME). Methods: The aim of the study was to contrast the differences in targeted genomics, TIME and survival between UC and UC-OGC. TIME was assessed via H&E, bulk RNA sequencing (RNA-seq), and multiplex immunofluorescence (mIF). Results: We identified 47 adult consecutive patients with UC (n=32) and UC-OGC (n=15) treated at Michigan Medicine between 2005 and 2021. The demographics, presenting symptoms, tumor size, and CA 19-9 were similar (p&gt;0.05) between the two cohorts. In patients with advanced stage, median overall survival (OS) was 2.1 months (n=19) for UC vs 9.0 months (n=2) for UC-OGC (p=0.42). Thirteen patients from each cohort underwent resection, with median OS 1.84 years vs 11.92 years in UC vs UC-OGC, respectively (p=0.08). Median OS for all patients with UC (n=32) was 0.40 years compared to 10.82 years in UC-OGC (n=15) (p=0.003). The genomic landscape was similar in UC (n=9), UC-OGC (n=5) and PDAC (TCGA; n=159). KRAS and TP53 mutations were the most common alterations identified along with CDKN2A and SMAD4. RNA-seq demonstrated few differentially expressed genes between UC (n=7) and UC-OGC (n=3). Deconvolution with CIBERTSORT-X using the LM22 dataset demonstrated significantly increased antigen-presenting cells (APCs), specifically M2 macrophages, decreased cytotoxic T-cells, and decreased regulatory T cells in UC and UC-OGC tumors compared to PDAC. These findings were confirmed as significant (p&lt;0.5) by multiplex mIF. Though UC (n=13) and UC-OGC (n=5) tumors had many similarities in their TIME, notable differences included decreased regulatory T cells (p=0.36) and a trend toward decreased M2 macrophages in UC-OGC tumors compared to UC (p=0.19). Conclusions: In this institutional series of pancreas UC with and without OGC, median OS in patients with UC-OGC was longer as compared to UC in both advanced and resected patients. Interestingly, there were significant differences in the TIME but not in the genomic profiles. Increased pro-tumorigenic M2 macrophage infiltration and decreased Tregs in the TIME of UC/UC-OGC compared to PDAC suggests a potential role of macrophage inhibitors and other immune-modulatory therapies in combination with chemotherapy for these rare variants of pancreatic cancer.
Citation Format: Jamie N. Mills, Valerie Gunchick, Jiaqi Shi, Aaron Udager, Timothy Frankel, Mark M. Zalupski, Vaibhav Sahai. Analysis of tumor immune microenvironment and clinical outcomes in undifferentiated pancreatic carcinomas with and without osteoclast-like giant cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C013.