Tumoral Lymphocytic Infiltration and Expression of the Chemokine CXCL10 in Breast Cancers from the Ontario Familial Breast Cancer Registry

Abstract

Purpose Breast carcinomas, including basal and hereditary cases, often present with a prominent tumoral lymphocytic infiltrate (LI). Chemokines could play a role in attracting these cells and contribute to tumor progression. We explored tumoral expression of CXCL10 and determined the relationship between CXCL10 and LI in a cohort of breast cancers. Experimental Design Using tissue microarrays of 364 breast tumors we evaluated expression of CXCL10 and its receptor, CXCR3, in relation to histopathologic features, biomarkers and lymphocyte markers. Additionally, we overexpressed CXCL10 and CXCR3 in MCF7 breast cancer cells and monitored T-lymphocyte migration and invasion. Results Forty-five percent of tumors expressed CXCL10 and a significant association was found with CXCR3 and LI. Further characterization of the LI revealed an association with CXCL10 expression for peritumoral CD4+ and CD8+ lymphocytes. CD8+ intratumoral lymphocytes, FOXP3+ Tregs and T-BET+ Th1 cells were associated with BRCA1 and basal tumors. Conditioned media from MCF7 cells overexpressing both CXCL10 and CXCR3 increased T-lymphocyte migration and invasion. Conclusions Our findings suggest that CXCL10 may act in a paracrine manner, affecting the tumor microenvironment, and in an autocrine manner, acting on the tumor cells themselves and may play a role in tumor invasiveness and progression. The CXCL10-CXCR3 axis can serve as a potential target in BRCA1 and basal breast cancers which present with a prominent LI and a poor prognosis.

Validation of Intratumoral T-bet+ Lymphoid Cells as Predictors of Disease-Free Survival in Breast Cancer

“…This is despite being associated with adverse clinicopathologic features, including larger tumor size, higher histologic grade, hormone receptor negativity, and the basal phenotype. The data from this independent cohort of women unselected for family history add to the findings from our previous study with a cohort of women with familial breast cancer which had examined expression of the chemokine CXCL10 and tumoral lymphocytic infiltration (30). The familial cohort included tumors from patients with a strong family history of breast cancer, a significant proportion of whom carry a germline BRCA mutation.…”

“…First, because of our prior findings of the prognostic significance of intratumoral T-bet þ lymphoid cells in the Breast Cancer Family Registry, Ontario site (30), and second, because we used TMAs in this study. TMAs preferentially include areas rich in tumor cells, and peritumoral areas may not be represented consistently, thereby introducing a potential bias in peritumoral T-bet þ lymphoid cell counts.…”

“…Furthermore, high numbers of T-bet þ intratumoral lymphoid cells have been found to correlate with improved outcome in gastric cancer (27) and in high-grade cervical intraepithelial neoplasia (28). In a cohort of women with familial breast cancer from the Ontario site of the Breast Cancer Family Registry (29), studied for expression of chemokine CXCL10 and tumoral lymphocytic infiltration, we observed that T-bet þ lymphocytes were associated with the basal molecular subtype as well as with morphologic features characteristic of such tumors, including high-grade, p53 expression, ER negativity, CK5 positivity, and EGFR positivity (30). Despite the association with an aggressive phenotype, T-bet positivity was associated with a good prognosis.…”

“…The mean, median, and range of intratumoral T-bet þ lymphoid cells were 7.4, 0.0, and were seen in 48 tumors, whereas 566 tumors (92.2%) had low or absent T-bet þ lymphoid cells. We performed analyses for intratumoral T-bet þ cells because this localization proved to be prognostically relevant in our previous study (30).…”

Enabling T Cell Recruitment to Tumours as a Strategy for Improving Adoptive T Cell Therapy

“…52 Mechanisms include pathologic vascularisation limiting T cell influx and extravasation, 53 selective expression or repression of integrins, or production of chemokines excluding T cell attraction. [54][55][56][57][58] Along these lines, even T cells that have managed to enter tumour tissue are limited in their activity due to a lack of tumour recognition. The latter being due to heterogeneous target expression, downregulation of expression, antigen loss variants (as a result of either self-mimicry or tolerance) or impairments on antigen processing and presentation.…”