Unique Ectopic Lymph Node-Like Structures Present in Human Primary Colorectal Carcinoma Are Identified by Immune Gene Array Profiling

Abstract

We hypothesized that immune gene-related signatures would predict the presence of unique histological features of lymphoid cell infiltrates in colorectal carcinoma (CRC) that correlate with clinical parameters. Metagene analysis with gene chip technology was performed on 326 CRCs, which were then sorted by low versus high gene scores. Microscopically, CRCs with a high gene score revealed a marked host immune response organized, remarkably, as lymphoid follicles. Proliferation involved both B and T cells. In every case, the presence of CD79a(+) B-cell precursors was identified, suggesting that the lymphoid follicles represent newly formed, ectopic lymph node-like structures. CD21(+) dendritic cells were present within the follicular germinal centers, and CD3(+) T cells were localized mainly in the parafollicular cortex zone surrounding the B-cell area of the follicles. A strong correlation between a 12-chemokine gene subset of the molecular profile and the presence of ectopic lymph node-like structures was associated with better patient survival independent of tumor staging, site location, microsatellite instability or stability, and patient treatment. These findings suggest beneficial, intratumoral immune cell priming and raise the possibility of immunotherapy intervention decisions based on molecular signatures that can identify the presence of tumor-localized, ectopic lymph node-like structures.

Priming the pancreatic cancer tumor microenvironment for checkpoint-inhibitor immunotherapy

“…The aggregates were composed of na€ ıve and activated T cells, B cells and innate antigen-presenting cells (APCs); and resembled ectopic lymph node-like structures observed in immunotherapy na€ ıve patients with melanoma, colon cancer and NSCLC. [14][15][16][17] Lymphoid aggregates formed regardless of whether GVAX was given with or without Cy. However, lower numbers of FoxP3 C Tregs were observed in tumors from patients treated with the combination of GVAXCCy indicating that low-dose Cy reduces Treg levels within the TME.…”

RNA biomarkers in colorectal cancer

“…This leads to inaccurate 76 prognostication for individual patients and clinical understaging of 77 approximately one third of stage II patients [3]. Hence a subgroup 78 of patients with presumed early CRC harbours a minimal, but clin- 79 ically significant amount of occult disease that is currently unde-80 tectable; although an emerging understanding of CRC biology is 81 beginning to identify molecular markers that may improve risk 82 assessment and treatment choices for these patients. 83 The survival benefit of adjuvant chemotherapy in stage II CRC 84 remains unproven [ Cancer may have spread through the mucosa of the colon wall to the submucosa and muscle layer, and has spread to one to three nearby lymph nodes or tissues near the lymph nodes (IIIA), through the serosa but not to nearby organs (IIIB) or through the serosa to nearby organs and to one or more nearby lymph nodes or to tissues near the lymph nodes.…”

Hyperactive gp130/STAT3‐driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development

“…Detection of a TLS‐associated gene signature may therefore act as a reliable prognostic indicator of patient outcome. Notably, the expression of TLS‐related genes including CXCL13 , CCL19 and CCL21 , has been linked with a good prognosis in colorectal cancer14, 15 and melanoma 13. Interestingly, expression of a 3‐gene TLS signature comprising CXCL13 , CCL19 and CCL21 was increased in patients with advanced GC.…”

“…TLSs can develop in tissues where persistent inflammation is present, and a correlation between high TLS densities and prolonged patient survival has been reported for several cancers including breast,5, 6 lung,7, 8 melanoma,9 pancreatic10 and colorectal 11, 12. TLS gene signatures, that include homeostatic chemokines such as CXCL13 , CCL19 and CCL21 , have the potential to represent prognostic indicators of cancer progression in melanoma13 and colorectal cancer 14, 15. Several studies propose that tumour‐associated TLSs provide a local environment for establishing and maintaining anti‐tumour immunity 4, 12.…”