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.
Highlights
The immune response to cancer, and colorectal cancer (CRC), has profound molecular, biological and clinical implications
In multivariate statistical models predicting survival, Crohn’s-like lymphoid reaction (CLR) had a greater impact on survival prediction than conventional histologic parameters such as tumor differentiation and venous invasion [13]; tumor infiltrating lymphocytes (TILs) [7]; or microsatellite instability [3]
It has been suggested that CLR has three maturation stages with functional and prognostic implications: [1] Early tertiary lymphoid structures (TLS), composed of dense lymphocytic aggregates without follicular dendritic cells (FDCs), [2] Primary follicle-like TLS, having FDCs but no germinal centers (GC) reaction, and
Summary
The immune response to cancer, and colorectal cancer (CRC), has profound molecular, biological and clinical implications. It has been suggested that CLR has three maturation stages with functional and prognostic implications: [1] Early TLS, composed of dense lymphocytic aggregates without follicular dendritic cells (FDCs), [2] Primary follicle-like TLS, having FDCs but no GC reaction, and [3] Secondary follicle-like TLS, having active GCs [14] These histologic findings may be altered in the context of neoadjuvant chemotherapy or steroid treatment, as demonstrated in squamous cell lung cancer [44]. This is supported by the increased intratumoral lymphocytic infiltrate and gene expression signatures of cytotoxicity and DCs that are associated with CLR [38], as well as similar T-cell repertoires among CLR and TILs [52]. Several cytokines, including CCL21 through the activation of CCR7 [80, 81], CCL5 and CXCL10 [82], have been implicated in metastatic lymphangiogenesis as well as the formation and maintenance of CLR and other tumor-specific immune responses
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