# Comprehensive Characterization of the Immune Microenvironment of Colorectal and Gastric Signet Ring Cell Cancer

## TL;DR

This study shows that the immune environments of colorectal and gastric signet ring cell cancers are different from other cancers, with IL13RA2 as a possible target for treatment.

## Contribution

The study identifies IL13RA2 as a novel potential biomarker and therapeutic target for colorectal signet ring cell cancer.

## Key findings

- The immune gene expression profiles of SRCC differ significantly from non-SRCC tumors.
- IL13RA2 is a potential biomarker and therapeutic target for colorectal SRCC.
- SRCC tumors show increased innate immune activity and CD8+ cell presence, suggesting immune evasion.

## Abstract

What are the main findings?
The immune components of gastric and colorectal SRCCs are distinct from their corresponding non-SRCC counterparts.IL13RA2 was identified as a potential biomarker and therapeutic target candidate for colorectal SRCC.

The immune components of gastric and colorectal SRCCs are distinct from their corresponding non-SRCC counterparts.

IL13RA2 was identified as a potential biomarker and therapeutic target candidate for colorectal SRCC.

What are the implications of the main findings?
Gastric and colorectal SRCC tumors likely employ immune evasion mechanisms.Overall, our descriptive study highlights pathways (IL-13, complement) that may be targeted for drug development in SRCC.

Gastric and colorectal SRCC tumors likely employ immune evasion mechanisms.

Overall, our descriptive study highlights pathways (IL-13, complement) that may be targeted for drug development in SRCC.

The reasons for the aggressive clinical phenotype of signet ring cell carcinoma (SRCC) have not been fully elucidated. Previous studies suggest similarities in the genotype of colorectal and gastric SRCC and a clear distinction from non-SRCC. The immune microenvironments of gastric and colorectal SRCC have not been comprehensively examined. We isolated RNA from formalin-fixed, paraffin-embedded (FFPE) sections of 34 tumor specimens, 10 colorectal SRCC, 24 gastric SRCC, 4 non-SRCC colorectal (CCC), and 3 gastric adenocarcinoma (GCC) samples. The PanCancer Immune Profiling Panel was used to evaluate the expression of 770 immune-related genes. We compared the expression profiles of colorectal and gastric SRCC and non-SRCC adenocarcinoma. We found that the immune-related gene expression profiles (GEPs) of colorectal SRCC (CR-SRCC) and gastric SRCC (G-SRCC) were distinct from the non-SRCC. A total of 127 genes were upregulated and 32 downregulated in CR-SRCC compared to CCC. Only two genes (CCL27 and LAIR2 reached statistical significance (p-adj < 0.05)) among the differentially expressed genes in G-SRCC compared to GCC. None of the clinically relevant immune checkpoints were significantly differentially expressed in SRCC vs. non-SRCC. Overall, we noted a relative abundance of CD8+ cells in CR-SRCC and G-SRCC and relative overexpression of genes involved in innate immune response including the complement pathway. Finally, we identified IL13RA2 as a potential biomarker and therapeutic target candidate for CR-SRCC. The immune microenvironments of CR-SRCC and G-SRCC are distinct from non-SRCC. Broadly, both CR-SRCC and G-SRCC are characterized by a complex immune microenvironment that features cytotoxic cells and innate immune activity that may facilitate immune evasion.