{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T19:17:18Z","timestamp":1785352638296,"version":"3.55.0"},"reference-count":36,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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 &lt; 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.<\/jats:p>","DOI":"10.3390\/cells15010030","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T14:05:22Z","timestamp":1766498722000},"page":"30","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Comprehensive Characterization of the Immune Microenvironment of Colorectal and Gastric Signet Ring Cell Cancer"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5246-3371","authenticated-orcid":false,"given":"Jianqing","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Collingwood","sequence":"additional","affiliation":[{"name":"Department of Clinical Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sameer","family":"Al Diffalha","sequence":"additional","affiliation":[{"name":"Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah Della","family":"Manna","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2317-7082","authenticated-orcid":false,"given":"Ravi Kumar","family":"Paluri","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3695-8192","authenticated-orcid":false,"given":"Haider A.","family":"Mejbel","sequence":"additional","affiliation":[{"name":"Department of Pathology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olumide","family":"Gbolahan","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Benesch, M.G.K., and Mathieson, A. (2020). Epidemiology of Signet Ring Cell Adenocarcinomas. Cancers, 12.","DOI":"10.3390\/cancers12061544"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"819","DOI":"10.4251\/wjgo.v8.i12.819","article-title":"Signet ring colorectal carcinoma: Do we need to improve the treatment algorithm?","volume":"8","author":"Tamhankar","year":"2016","journal-title":"World J. Gastrointest. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e2236666","DOI":"10.1001\/jamanetworkopen.2022.36666","article-title":"Incidence and Survival in Synchronous and Metachronous Liver Metastases from Colorectal Cancer","volume":"5","author":"Reboux","year":"2022","journal-title":"JAMA Netw. Open"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.dld.2021.01.021","article-title":"Differences in the management and survival of metastatic colorectal cancer in Europe. A population-based study","volume":"53","author":"Bouvier","year":"2021","journal-title":"Dig. Liver Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10460","DOI":"10.1038\/s41598-020-67388-6","article-title":"Clinicopathological characteristics and survival in colorectal signet ring cell carcinoma: A population-based study","volume":"10","author":"Yang","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"332","DOI":"10.5217\/ir.2015.13.4.332","article-title":"Clinical Features and Prognosis of Resectable Primary Colorectal Signet-Ring Cell Carcinoma","volume":"13","author":"Lee","year":"2015","journal-title":"Intest. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1245\/s10434-014-4159-7","article-title":"Prognostic significance and molecular features of signet-ring cell and mucinous components in colorectal carcinoma","volume":"22","author":"Inamura","year":"2015","journal-title":"Ann. Surg. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1002\/ijc.28981","article-title":"Colorectal signet-ring cell carcinoma: Benefit from adjuvant chemotherapy but a poor prognostic factor","volume":"136","author":"Hugen","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Zhao, S., Lv, L., Zheng, K., Tian, Y., Zheng, J.C., and Jiang, C.G. (2021). Prognosis and Biological Behavior of Gastric Signet-Ring Cell Carcinoma Better or Worse: A Meta-Analysis. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.603070"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ma, J., Meng, Y., Zhou, X., Guo, L., and Fu, W. (2022). The Prognostic Significance and Gene Expression Characteristics of Gastric Signet-Ring Cell Carcinoma: A Study Based on the SEER and TCGA Databases. Front. Surg., 9.","DOI":"10.3389\/fsurg.2022.819018"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3455","DOI":"10.1038\/s41388-022-02350-6","article-title":"Molecular profiling of signet-ring-cell carcinoma (SRCC) from the stomach and colon reveals potential new therapeutic targets","volume":"41","author":"Puccini","year":"2022","journal-title":"Oncogene"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"38850","DOI":"10.18632\/oncotarget.16407","article-title":"The PD-1, PD-L1 expression and CD3+ T cell infiltration in relation to outcome in advanced gastric signet-ring cell carcinoma, representing a potential biomarker for immunotherapy","volume":"8","author":"Jin","year":"2017","journal-title":"Oncotarget"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Nielsen, T., Wallden, B., Schaper, C., Ferree, S., Liu, S., Gao, D., Barry, G., Dowidar, N., Maysuria, M., and Storhoff, J. (2014). Analytical validation of the PAM50-based Prosigna Breast Cancer Prognostic Gene Signature Assay and nCounter Analysis System using formalin-fixed paraffin-embedded breast tumor specimens. BMC Cancer, 14.","DOI":"10.1186\/1471-2407-14-177"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nbt1385","article-title":"Direct multiplexed measurement of gene expression with color-coded probe pairs","volume":"26","author":"Geiss","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s40425-015-0088-7","article-title":"nCounter((R)) PanCancer Immune Profiling Panel (NanoString Technologiess, Inc., Seattle, WA)","volume":"3","author":"Cesano","year":"2015","journal-title":"J. Immunother. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Chen, Y., Sun, Z., Chen, W., Liu, C., Chai, R., Ding, J., Liu, W., Feng, X., Zhou, J., and Shen, X. (2021). The Immune Subtypes and Landscape of Gastric Cancer and to Predict Based on the Whole-Slide Images Using Deep Learning. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.685992"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0140-6736(21)00797-2","article-title":"First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): A randomised, open-label, phase 3 trial","volume":"398","author":"Janjigian","year":"2021","journal-title":"Lancet"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1007\/s10120-021-01195-4","article-title":"Optimized PD-L1 scoring of gastric cancer","volume":"24","author":"Eschbach","year":"2021","journal-title":"Gastric Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e2200179","DOI":"10.1200\/PO.22.00179","article-title":"The Prevalence and Prognosis of Microsatellite Instability-High\/Mismatch Repair-Deficient Colorectal Adenocarcinomas in the United States","volume":"7","author":"Gutierrez","year":"2023","journal-title":"JCO Precis. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Bao, D., Zhang, C., Li, L., Wang, H., Li, Q., Ni, L., Lin, Y., Huang, R., Yang, Z., and Zhang, Y. (2021). Integrative Analysis of Complement System to Prognosis and Immune Infiltrating in Colon Cancer and Gastric Cancer. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.553297"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3077","DOI":"10.2147\/DMSO.S311725","article-title":"Complement C7 is Specifically Expressed in Mesangial Cells and is a Potential Diagnostic Biomarker for Diabetic Nephropathy and is Regulated by miR-494-3p and miR-574-5p","volume":"14","author":"Guo","year":"2021","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Markiewski, M.M., Daugherity, E., Reese, B., and Karbowniczek, M. (2020). The Role of Complement in Angiogenesis. Antibodies, 9.","DOI":"10.3390\/antib9040067"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"100068","DOI":"10.1016\/j.mcpro.2021.100068","article-title":"Proteomic Profiling of Gastric Signet Ring Cell Carcinoma Tissues Reveals Characteristic Changes of the Complement Cascade Pathway","volume":"20","author":"Fan","year":"2021","journal-title":"Mol. Cell. Proteom."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.5306\/wjco.v15.i9.1126","article-title":"Immunosuppressive tumor microenvironment in gastric signet-ring cell carcinoma","volume":"15","author":"Xie","year":"2024","journal-title":"World J. Clin. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/bjc.2017.168","article-title":"Molecular profiling of signet ring cell colorectal cancer provides a strong rationale for genomic targeted and immune checkpoint inhibitor therapies","volume":"117","author":"Alvi","year":"2017","journal-title":"Br. J. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.celrep.2016.03.075","article-title":"Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma","volume":"15","author":"Giannakis","year":"2016","journal-title":"Cell Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6412","DOI":"10.1158\/1078-0432.CCR-09-1438","article-title":"Lymphocytic reaction to colorectal cancer is associated with longer survival, independent of lymph node count, microsatellite instability, and CpG island methylator phenotype","volume":"15","author":"Ogino","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3544","DOI":"10.1200\/JCO.2024.42.16_suppl.3544","article-title":"The tumor immune microenvironment features and their prognostic value in rectal and sigmoid colon signet-ring cell carcinoma","volume":"42","author":"An","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1053\/j.gastro.2023.03.008","article-title":"Single-Cell Profiling of Tumor Immune Microenvironment Reveals Immune Irresponsiveness in Gastric Signet-Ring Cell Carcinoma","volume":"165","author":"Chen","year":"2023","journal-title":"Gastroenterology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2985","DOI":"10.1038\/s41467-023-38426-4","article-title":"Single-cell analysis of gastric signet ring cell carcinoma reveals cytological and immune microenvironment features","volume":"14","author":"Zhao","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Lawal, B., Tseng, S.H., Olugbodi, J.O., Iamsaard, S., Ilesanmi, O.B., Mahmoud, M.H., Ahmed, S.H., Batiha, G.E., and Wu, A.T.H. (2021). Pan-Cancer Analysis of Immune Complement Signature C3\/C5\/C3AR1\/C5AR1 in Association with Tumor Immune Evasion and Therapy Resistance. Cancers, 13.","DOI":"10.3390\/cancers13164124"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1158\/1541-7786.MCR-10-0225","article-title":"Cancer and the complement cascade","volume":"8","author":"Rutkowski","year":"2010","journal-title":"Mol. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Talaat, I.M., Elemam, N.M., and Saber-Ayad, M. (2022). Complement System: An Immunotherapy Target in Colorectal Cancer. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.810993"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2780","DOI":"10.1158\/0008-5472.CAN-11-4090","article-title":"High expression of IL-13 receptor alpha2 in colorectal cancer is associated with invasion, liver metastasis, and poor prognosis","volume":"72","author":"Barderas","year":"2012","journal-title":"Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.gendis.2023.01.027","article-title":"IL-13\/IL-13RA2 signaling promotes colorectal cancer stem cell tumorigenesis by inducing ubiquitinated degradation of p53","volume":"11","author":"He","year":"2024","journal-title":"Genes Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1038\/s41416-018-0259-7","article-title":"An IL13Ralpha2 peptide exhibits therapeutic activity against metastatic colorectal cancer","volume":"119","author":"Bartolome","year":"2018","journal-title":"Br. J. Cancer"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/1\/30\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T05:13:36Z","timestamp":1766726016000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/1\/30"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,23]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["cells15010030"],"URL":"https:\/\/doi.org\/10.3390\/cells15010030","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,23]]}}}