Presence of tertiary lymphoid structures determines the level of tumor-infiltrating lymphocytes in primary breast cancer and metastasis

Abstract

The level of tumor-infiltrating lymphocytes and presence of tertiary lymphoid structures are significant prognostic and predictive factors in primary breast cancer. However, the understanding about differences in tumor-infiltrating lymphocytes and tertiary lymphoid structures at various metastatic sites or between primary breast tumors and metastatic sites is limited. A total of 335 cases of metastatic breast cancer from four metastatic sites (lung, liver, brain, and ovary) were included. We analyzed the percentages of tumor-infiltrating lymphocytes and presence of tertiary lymphoid structures in the primary and metastatic sites. The mean level of tumor-infiltrating lymphocytes in the lung metastases was higher than in the liver, brain, ovary, and matched primary tumors, while metastatic tumors of the liver and brain showed lower levels of tumor-infiltrating lymphocytes than primary tumors. Tertiary lymphoid structures were only found in the lung and liver, and in cases of brain metastases the change of tertiary lymphoid structures from present to absent significantly affected the level of tumor-infiltrating lymphocytes in metastases compared with that in matched primary tumors. Patients with a lower histological grade, hormone receptor positivity in primary tumors and metastases, a lower level of tumor-infiltrating lymphocytes and absence of tertiary lymphoid structures in primary tumors, a higher level of tumor-infiltrating lymphocytes and presence of tertiary lymphoid structures in metastases, and lung metastases showed significantly better overall survival. Our results showed that metastatic breast tumors in the lung had more tumor-infiltrating lymphocytes than did tumors at other sites and matched primary tumors. In addition, the presence of tertiary lymphoid structures in metastatic sites is a critical factor for the level of tumor-infiltrating lymphocytes.

Tertiary lymphoid structures in the era of cancer immunotherapy

“…This is notably the case for tumours occurring in immunologically privileged sites, such as the brain (glioblastoma and lower-grade glioma) and the eye (uveal melanoma), although tumours occurring in testis (testicular germ cell tumours) exhibit a remarkably high expression of the TLS signature. In accordance with these findings, healthy brain tissues express low levels of CXCL12, CXCL13 and CCL21, and brain metastases from melanoma and breast cancer contain no or very few TLSs 58,59 . Other malignancies also presented very low expression of this signature: adrenocortical carcinoma, pheochromocytoma or paraganglioma, and most kidney carcinoma histotypes with the exception of clear-cell renal cell carcinoma.…”

“…In melanoma, it has been reported that only skin metastases exhibit fully developed TLSs with proliferating B cells and AID expression; by contrast, FDCs were detected in some lung, muscle and gut metastases but not in brain metastases 58 . In breast cancer, analysing a large cohort of 355 metastases from 4 metastatic sites (lung, liver, brain and ovary), Lee et al 59 reported that TLSs can be found in lung and liver metastases but not in brain and ovarian metastases.…”

“…When present at metastatic sites, TLSs have the same characteristics as in primary sites. Their density correlates with high T cell infiltration in the tumour, often with a T H 1 cell and cytotoxic T cell skewing 10,48,59,82,96,106,107 . The role of B cells is beginning to be addressed.…”

“…Finally, as for their prognostic impact, TLSs in metastatic sites parallel that of primary tumours. Their density correlates with prolonged survival in patients with lung 106 and liver 96 metastases from colorectal cancer, lung metastases from breast cancer 59 and omental meta stases from high-grade serous ovarian cancer 48 , and DC-LAMP + DC density correlated with a shorter survival in lung metastases from clear-cell renal cell carcinoma 106 (TABLe 2). Altogether, data emerging from studies specifically looking at metastatic sites have illustrated the diversity of situations but support the general findings established with TLSs in primary tumours, showing that the tumour type, the organ, the degree of TLS maturation, their location with the TME and the inflammatory context of the cancerous site are essential parameters for their clinical impact.…”

Graph-based description of tertiary lymphoid organs at single-cell level

“…In breast cancer, TLO detection is recently becoming even more relevant as there are correlations between TLOs and other, therapeutically relevant infiltration patterns [48,49].…”