Abstract P5-04-02: Tumor Associated High Endothelial Venules (HEV) Predict Lymphocyte Infiltration and Breast Cancer Patients Clinical Outcome

Abstract

Abstract Even if lymphocyte presence within tumor tissues and its impact on cancer patient prognosis have been well documented past few years, the type of tumor vessels governing infiltration of effector cells into tumors remain to be determined. High endothelial venules (HEV) are specialized vessels for lymphocyte recruitment physiologically present in secondary lymphoidorgans also found in chronic inflammation that may impact lymphocyte recruitment and cancer patient's clinical outcome. We recently identified HEV like vessels in the peritumoral stroma of human solid tumors including melanomas, breast, colon, ovarian, and lung carcinomas. In order to better analyse the functional consequence of HEV presence within human solid tumors, we quantified HEV and tumor infiltrating lymphocytes by immunohistochemistry on serial tumor sections of 146 breast cancer patients. We demonstrate that HEV like vessels density within tumor stroma is an important predictor of CD3+, CD8+ T and B lymphocyte tumor infiltration suggesting an active role played by these vessels in peripheral blood lymphocyte migration into tumors. The breast tumor infiltrating lymphocyte phenotype associated with HEV presence was further characterized by large scale flow cytometry analysis in 30 freshly operated breast tumors. Breast tumors with a high density of HEV (HEVhi) have increased numbers of effector memory T cells (CD45RA-CD62L-) that display an activated mature phenotype (CD69+, Granzyme A+, Granzyme B+, perforin+). T cells with a naïve (CD45RA+CD62L+) and a central memory (CD45RA-CD62L+) phenotype are also specifically increased within HEVhi tumors as compared to HEVlo tumors. Finally, we analyzed the prognostic value of HEV in a retrospective cohort of 146 invasive breast cancer patients and demonstrate that HEV density within tumor stroma is an independent predictor of good clinical outcome. Indeed, HEVhi patients have a significantly longer metastasis free survival (MFS) (p< 0,004), disease free survival (DFS) (P<0,012) and overall survival (OS) (P<0,023) than HEVlo patients. HEV like vessels, through the recruitment of high number of T lymphocytes and B lymphocytes from the periphery could limit the dissemination of primary breast tumors and prevent metastatic recurrence. Therefore, signals and cells that stimulate HEV differentiation within tumor stroma represent important solid tumors therapeutic target to modulate immune infiltration and patient's clinical outcome. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-04-02.