76: A Unique Immunosuppressive Macrophage Transcriptional Signature Is a Poor Prognostic Biomarker in Primary Upper GI Cancer

Thursday, March 10, 2022

4:11 PM – 4:19 PM CST

Location: Trinity Ballroom

Abstract Presenter(s)

Kevin M. Sullivan, MD

Fellow
City of Hope
Pasadena, California, United States

Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.

Participants should be aware of the following financial/non-financial relationships:

Kevin M. Sullivan, MD: I do not have any relevant financial / non-financial relationships with any proprietary interests.

Introduction: Gastric cancer (GC) and esophageal cancer (EC) are significant causes of cancer morbidity and mortality. Macrophages are associated with poor outcomes, but a signature of M2 transcriptional genes that is prognostic in patients with primary upper GI cancer has not been defined.

Methods: We derived a novel transcriptomic immune signature from published differentially expressed genes that distinguish M1 versus M2 macrophages in the peripheral blood. To evaluate the clinical significance of our M2-macrophage gene panel we used UCSC Xena to analyze TCGA Stomach Cancer and TCGA Esophageal Cancer. We investigated both M1- and M2-macrophage signatures (M1 signature: CCR7, IL2RA, CXCL11, CCL19, CXCL10, PLA1A, PTX3 and M2 signature: MRC1, MS4A4A, CD36, CCL13, CCL18, CCL23, SLC38A6, FGL2, FN1, MAF) and a T cell cytolytic signature (GZMA, GZMB, GZMH, GZMM, PRF1). We compared gene expression to pathologic stage and histological subtype. Log-rank test was used to compare Kaplan-Meier curves for overall survival (OS) and disease-free interval (DFI).

Results:

A total of 341 GC and 142 EC entries were analyzed. Higher expression of the M2-macrophage signature in GC was associated with diffuse type adenocarcinoma and mucinous type intestinal adenocarcinoma, compared to tubular and papillary type intestinal adenocarcinoma (p< 0.001). Higher M2-macrophage signature expression was associated with late stage (Stage II or above) compared to early-stage GC (stage I) (p=0.02). In EC, a high M2-macrophage signature was associated with higher pT stage (p< 0.001). A low M2-macrophage signature was associated with improved 5-year OS for GC (p=0.03, [Fig 1A]), and a significantly improved 5-year DFI for both GC and EC (p=0.04 for GC, p=0.01 for EC [Fig 1B]). Cytolytic T cell signature and M1 macrophage signature were not associated with stage or survival.

Conclusions: A unique transcriptional signature derived from peripheral blood immunosuppressive M2 macrophage phenotype is associated with higher pathologic staging and with worse outcomes in GC and EC primary tumors. These M2 defining molecular biomarkers of GC and EC has the potential to serve as targets of novel immune-therapeutic strategies.

Learning Objectives:

Upon completion, participant will be able to identify transcriptional differences between M1 macrophages and M2 macrophages
Upon completion, participant will be able to describe differences in the clinicopathologic features of upper GI cancers with high M2 macrophage transcriptional signature expression
Upon completion, participant will be able to describe the effect on survival and disease free interval in upper GI cancers with high M2 macrophage transcriptional signature expression