Intratumoral, rather than stromal, CD8+ T cells could be a potential negative prognostic marker in invasive breast cancer patients

Abstract

BACKGROUND: Tumor infiltrating lymphocytes (TILs) are widely considered a key sign of the immune interaction between host and tumor, and potentially prognostic biomarkers of good or bad outcome in many cancers, included invasive breast cancer (BC). However, results about the association between TIL typology, location and BC prognosis, are controversial. The aim of the study was to evaluated the prognostic significance of TIL subtypes (CD4+, CD8+, FOXP3+ T cells) and their location (stromal “s” and intratumoral “i” CD4+ and CD8+) in BC patients, focusing on the association between these markers and immunocheckpoint molecules such as cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death ligand 1 (PD-L1) and its receptor (PD-1). METHODS: CD4+, CD8+, FOXP3+, CTLA4+, PD-L1+ and PD-1+ expression was examined by immunohistochemistry on tissue microarrays (TMAs) from 180 BC patients. Univariate and Kaplan–Meier analyses of disease free survival (DFS) were performed to evaluate the prognostic significance of marker expression. RESULTS: Total CD8+ T cells were not significantly associated with DFS. Differently, patients with iCD8+ and sCD8+ overexpression showed a trend toward respectively a worse (P = .050) and a better 5-years DFS (P = .064). Interestingly, TIL expression of both PD-1+ and PD-L1+, was significantly associated with iCD8+ (P = .0004; P < .0001 respectively), while only TIL expression of PD-1 was associated with sCD8+ (P = .001). CONCLUSION: Our data show that iCD8+ T cells, but no sCD8+ T cells identify a subgroup of patients with poor DFS and this could be due to the overexpression of PD-L1/PD-1 pathway.

Comprehensive evaluation of methods to assess overall and cell-specific immune infiltrates in breast cancer

“…3a). We tested the possibility that higher itTIL may lead to more pronounced inflammatory gene expression than sTIL as itTIL may have a crucial anti-tumor role [40][41][42][43][44]. Yet, we observed no higher correlation between intratumoral infiltration and inflammation-associated signatures (immune signatures, pink label Fig.…”

Levels of different subtypes of tumour-infiltrating lymphocytes correlate with each other, with matched circulating lymphocytes, and with survival in breast cancer

“…There is, again, support for this in the literature in the relatively few studies that have separately quantified in tumour nest and stromal compartments. For example, in an overwhelmingly ER-positive cohort, tumour nest but not stromal CD8 cells were shown to correlate with reduced survival [26]. Similarly, FoxP3+ T cells have been shown to predict poor survival when located within the tumour nests but not in stroma that is at least one cell away from tumour cells, although this was not broken down on ER status [27], and the correlation has also been reported specifically in ER-positive but not in ER-negative cases, although this study failed to differentiate between tumour compartments [28].…”

Clinicopathologic Characteristics of Breast Cancer According to the Infiltrating Immune Cell Subtypes

“…Although a previous study reported a contradictory result that increased CD8 + cells in TNBC were associated with better prognosis [ 15 ], the discordant result could be related to the fact that we investigated stromal CD8 + immune cells, while the previous study investigated intratumoral CD8 + immune cells. Moreover, whether intratumoral CD8 + immune cells are a positive or negative prognostic factor remains unclear, as a study by Catacchio et al has shown that intratumoral CD8 + immune cells are a negative prognostic factor in all breast cancers [ 41 ]. The association between CD8 + immune cells and breast cancer prognosis can be influenced by multiple factors, such as density, localization, and spatial distribution in TME [ 42 ].…”