Abstract
Tumor-infiltrating lymphocytes (TILs) in breast cancer are a key representative of the tumor immune microenvironment and have been shown to provide prognostic and predictive biomarkers. The extent of lymphocytic infiltration in tumor tissues can be assessed by evaluating hematoxylin and eosin (H&E)-stained tumor sections. We investigated tissue microarrays of 31 invasive breast cancer patients, looking at quantity and topological distribution of CD3+, CD8+, CD20+, Ki67+, FoxP3+ TILs and CD3+/FoxP3+, CD8+/FoxP3+ cell ratios. We separately evaluated TILs at the invasive edge and at the center of the tumor, to find any clinical implications of tumor heterogeneity. No statistically significant difference was found in quantity and distribution of both TIL subsets and TIL ratios, by comparing patients who suffered from a local or distant recurrence of the tumor (relapse group: 13 patients) with patients not showing cancer relapse (non-relapse group: 18 patients). In the whole sample, we observed three main statistically significant positive correlations: (1) between CD3+ and CD8+ T-cells; (2) between FoxP3+ and Ki67+ lymphocyte infiltration; (3) between CD3+/FoxP3+ cell ratio (C3FR) and CD8+/FoxP3+ cell ratio (C8FR). Tumor heterogeneity and stronger positive TIL associations were found in the non-relapse group, where both CD3–CD8 and FoxP3-Ki67 inter-correlations were found to be significant at the center of the tumor, while the correlation between C3FR and C8FR was significant at the invasive edge. No correlations between TIL subsets were detected in the relapse group. Our findings suggest the existence of stronger inter-subtype lymphocytic networks in invasive breast cancer not showing recurrence. Further evaluations of clinical and topological correlations between and within TIL subsets are needed, in addition to the assessment of TIL quantification and distribution, in order to follow up on whether morphological evaluation of TILs might reveal the underlying lymphocytic functional connectivity and help relapse prediction.
Highlights
Breast cancer accounts for 25% of all cancers in developed countries [1] and is the first cancer world-wide affecting women, at a mean age of 64 years [2]
FoxP3 is more likely to be an indicator of tumor-induced immune evasion [31], since FoxP3+ cells are responsible for inactivation of tumor-specific immune defense [40,53] and autoreactive T lymphocytes, such as CD8+ cells [19,40,54]
Patients without relapse exhibited several significant correlations of both suppressor (CD3+, CD8+) and effector (FoxP3+) tumor-infiltrating lymphocytes (TILs), suggesting that strong lymphocytic networks, independently from their suppressor/effector nature, underpin tumor balance, with a less connected and wired tumor immune microenvironment potentially increasing the risk of relapse
Summary
Breast cancer accounts for 25% of all cancers in developed countries [1] and is the first cancer world-wide affecting women, at a mean age of 64 years [2]. TILs are widely considered to be a key indicator of the immune interaction between host and tumor, and potentially effective predictive biomarkers of cancer immunogenicity, clinical outcome, response to immunotherapy and other antitumor treatments [5,6,7,8,9,10,11]. Lymphocytic infiltrates have long been observed in breast cancer, only recent clinical trials have demonstrated the immunogenic nature of breast cancer and the potential role of host immunosurveillance in influencing tumor progression and treatment responses [5,8,12,13,14,15,16,17,18,19,20,21,22,23,24]. “suppressor” TIL subsets (e.g., FoxP3+, CD4+) can harbor immunosuppressive activity, promote tumor invasion and restrict the effectiveness of immunotherapeutic strategies [29,30]; on the other hand, “effector” TILs (e.g., CD3+, CD8+) have substantial anti-tumor and anti-proliferative capabilities, and have been found to be associated with improved pathological response and better clinical outcome [5,18,22,32,33,34,35,36,37,38]
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