High endothelial venules are rare in colorectal cancers but accumulate in extra-tumoral areas with disease progression

Abstract

Prolonged patient survival after surgical resection, is associated with a higher cytotoxic and memory T cell density within colorectal cancers (CRC). High endothelial venules (HEVs) are specialized blood vessels present in secondary lymphoid organs (SLO) that allow ingress of naïve and central memory T cells from the blood. It has been proposed that HEVs in tumors might serve as a similar route of entry for lymphocytes into the tumor and result in an improved prognosis. The present study aimed to characterize HEVs and their microenvironment in resected tumors from colorectal cancer patients (n = 62). We observed HEVs in association with lymphoid aggregates in 49 out of 62 patients. However, these HEV+ lymphoid aggregates were largely at the invasive margin of the tumor and although there was an association with lymphocytes and HEVs at the invasive margin (p = 0.002) there was only a very weak association with tumor infiltrating lymphocytes. Indeed, lymphoid aggregates were associated with more advanced disease (Dukes’ stage C) and did not indicate a favorable prognosis.

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

“…High densities of intra‐tumoural TLSs and HEV have been linked with enhanced local Th1 responses and improved patient survival 6, 50. By contrast, and consistent with the location of TLSs in our study of GC, the presence of extra‐tumoural TLSs in colorectal cancer did not yield a positive prognosis but reflected a pro‐inflammatory microenvironment surrounding tumours in advanced disease 18. Therefore, in some cancers extra‐tumoural TLSs may reflect a pathological consequence of inflammation‐associated tumourigenesis, rather than markers of an effective anti‐cancer response.…”

“…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.…”

Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer

“…35 In line with this observation, the presence of tertiary lymphoid structures in early stage CRC has revealed a favorable prognostic impact on tumor course, 11 even though the association between lymphoid aggregates (which are mostly extra-tumoral) and prognosis remains controversial. 53 The subset of Tfr cells is specialized in suppressing Tfh responses and inhibiting the organization of efficient lymphoid follicles. 12 Therefore, it is conceivable that Tfr play detrimental roles in tumor progression.…”

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

“…In this context, it is therefore surprising that ELFs arise in tumours at all. However, ELFs have been described in numerous cancers including colorectal,60, 88 rectal,89 breast,67, 90, 91 ovarian67, 92 and germ cell93 cancers, as well as melanoma,62, 67, 94 mucosal‐associated lymphoid tissue lymphoma39 and non‐small cell lung carcinoma95, 96 (NSCLC; see Dieu‐Nosjean et al . for a comprehensive review of ELFs in cancer9).…”