Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma

Abstract

Ectopic lymphoid-like structures (ELS) are often observed in cancer, yet their function is obscure. Although ELSs signify good prognosis in certain malignancies, we found that hepatic ELSs indicate poor prognosis in hepatocellular carcinoma (HCC). We studied an HCC mouse model, displaying abundant ELSs and found that they constitute immunopathological microniches, wherein progenitor malignant hepatocytes appear and thrive in a complex cellular and cytokine milieu until gaining self-sufficiency. Progenitor egression and tumor formation is associated with autocrine production of cytokines previously provided by the niche. ELSs develop upon cooperation between the innate and adaptive immune system which is facilitated by NF-κB activation and abolished by T cell depletion. These aberrant immune foci could be new targets for cancer therapy.

Tertiary Lymphoid Structures Associate with Tumour Stage in Urothelial Bladder Cancer

“…In ovarian, colorectal, breast and lung cancer, intra-tumoural B cells or those located within organized TLS are associated with favorable outcomes suggesting there anti-tumour role whereas their increased numbers are negatively correlated with melanoma, prostate, renal cell and hepatocellular carcinoma prognosis [16,19,24]. In these cancers where TLS are associated with poor prognosis it is speculated that these could act as the microniches providing a source of the complex cytokine factors required for tumour cell survival [19]. The underlying mechanisms driving TLS formation in tumour sites are currently an area of active research.…”

“…It must be noted that TLS are also speculated to be a mere bystander effect of inflammation within the TME and not as an active participant in mediating anti-tumour immune response in certain cancer sites [12,18]. Interestingly, a recent study on hepatocellular carcinoma describes these TLS as micro niches supporting tumour cell growth and survival [19]. TLS mimicking features of a canonical GC reaction, within an inflamed tissue and cancer are evidence supporting active adaptive immunity triggered within the tumor microenvironment.…”

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

“…Improved patient survival in non‐small‐cell lung carcinoma has also been linked with TLSs, where follicular B cells and plasma cells show antibody specificity to tumour antigens 8. However, TLS involvement and activity may only have prognostic value in certain stages of tumour development or for certain types of cancer 11, 18, 19. Thus, greater mechanistic insights are required to establish the link between TLS formation, tumour progression and clinical outcome.…”

TLS in Tumors: What Lies Within

“…Two recent articles using genetically engineered mouse models (GEMM) of lung cancer [5] and hepatocellular carcinoma (HCC) [6] shed light on TLS regulation and function and provide new insight on their role in cancer development.…”

“…Joshi et al [5] Finkin et al [6]developed an inflammation-driven HCC model by expressing constitutively the active form of IKK-B in hepatocytes to activate the NF-B pathway, a situation that occurs in common forms of chronic hepatitis in humans [6,8]. .…”