The Crohn's-Like Lymphoid Reaction to Colorectal Cancer-Tertiary Lymphoid Structures With Immunologic and Potentially Therapeutic Relevance in Colorectal Cancer

Abstract

The Crohn's-like lymphoid reaction (CLR) to colorectal cancer (CRC), a CRC-specific ectopic lymphoid reaction, is thought to play an important role in the host response to CRC. CLR is characterized by peritumoral lymphocytic aggregates that are found at the advancing edge of the tumor. Spatial and molecular characterization of CLR within the tumor microenvironment (TME) have uncovered a spectrum of peritumoral lymphoid aggregates with varying levels of organization and maturation. In early stages of CLR development, CD4+ T-cells cluster predominantly with mature antigen presenting dendritic cells. As CLR matures, increasing numbers of B-cells, as well as follicular dendritic cells are recruited to create lymphoid follicles. When highly organized, CLR resembles functional tertiary lymphoid structures (TLS), allowing for lymphocyte recruitment to the TME and promoting a tumor-specific adaptive immune response. CLR has been consistently associated with favorable prognostic factors and improved survival among CRC patients, often providing more prognostic information than current clinical staging systems. However, consensus is lacking regarding CLR scoring and it is not clinically assessed or reported. Differences between CLR and other cancer-associated lymphoid structures exist both in primary and metastatic disease, underscoring the need to characterize organ-specific TLS. Further research is needed to explore the role of CLR in predicting response to immunotherapy and to leverage CLR to promote immunotherapeutic strategies in CRC.

<p>A Rare Case of Moderately Differentiated Adenocarcinoma With PD-L1 Overexpression and a Heterogeneous LELC Component in the Ascending Colon</p>

“…The term CLR was coined by Graham and Appelman in 1990 23 and described as discrete lymphoid aggregates, some with germinal centers, mostly located in the muscularis propria and pericolonic adipose tissue beyond the advancing tumor edge. 24 Several cancers of Lynch syndrome were noted to be associated with dense Crohn's-like lymphoid aggregates; however, our case did not show MSI. In the present case, CLR consisted of CD20-positive B lymphocytes.…”

“…As CLR matures, increasing numbers of B-cells, as well as follicular dendritic cells, are recruited to create lymphoid follicles. 24 Our CLR consisted of B-cells and had a mature lymphoid structure with lymphoid follicle development.…”

“…Regarding immunological features, CLR has been consistently associated with increased tumor intraepithelial and stromal lymphocytic infiltrates, which appears to be independent of the MSI status. 14,24 CLR density is also correlated with peripheral immune markers, such as the absolute peripheral lymphocyte count and the lymphocyte to neutrophil ratio, which also carry prognostic significance. 15,24,25 In addition, CLR-promoting chemokines are inversely associated with the intratumoral expression of immune checkpoint molecules, including PD-1, PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).…”

Immunological potential of tertiary lymphoid structures surrounding the primary tumor in gastric cancer

“…Secondly, there were several weaknesses in the analysis of TLSs. It is difficult to distinguish TLSs from other lymphoid structures, such as Crohn's-like Lymphoid Reaction (CLR), as CLR has discrete lymphoid aggregates within the GC in colorectal cancer, they are mostly located in the muscularis propria and pericolonic adipose tissue beyond the advancing tumor edge, and they could be regarded as CRC-specific ectopic lymphoid structures (47). Lastly, it is important to analyze fibroblastic reticular cells and additional co-stimulatory molecules other than CD27/CD70, such as 4-1BB and OX40, which are associated with the promotion of effector CD4 + and CD8 + T-cell survival, and the formation of CD8 + T cell memory cells (48).…”

Rottlerin ameliorates DSS-induced colitis by improving intestinal barrier function via activation of the Epac-2/Rap-1 signaling pathway

“…Long-term inflammatory stimulation also raises the risk of colorectal cancer, causing grievous social and medical economic burdens. In recent years, with the continuous improvement of the economy, the incidence of CD has increased significantly [3] . The etiology and pathogenesis of CD are not completely clear, but intestinal mucosal immune homeostasis disorder, intestinal barrier dysfunction, bacterial infection and genetics are generally recognized as factors [4] .…”