Association between Intratumoral CD8+ T Cells with FoxP3+ and CD163+ Cells: A Potential Immune Intrinsic Negative Feedback Mechanism for Acquired Immune Resistance

Abstract

Acquired immune resistance (AIR) describes a situation in which cancer patients who initially responded clinically to immunotherapies, after a certain period of time, progress with their disease. Considering that AIR represents a feedback response of the tumor against the immune attack generated during the course of immunotherapies, it is conceivable that AIR may also occur before treatment initiation as a mechanism to escape endogenous adaptive antitumor immunity (EAAI). In the present study, we assessed the EAAI in paraffin-embedded breast primary tumor tissue samples and drew correlations with the clinical outcomes. In particular, we analyzed densities of CD8+ cells as elements mediating antitumor cytotoxicity, and of CD163+ and FoxP3+ cells as suppressor elements. We found a direct correlation between the densities of CD8+ cells and of CD163+ and/or FoxP3+ cells in the vast majority of patients’ tumors. Importantly, the vast majority of patients whose tumors were overpopulated by CD8+ cells developed AIR, which was characterized by high intratumoral CD163+ and/or FoxP3+ cell densities and reduced overall survival (OS). We also showed that AIR depends on the levels of CD8+ cell-ratios in the tumor center to the invasive margin. Our data suggest that tumors develop AIR only when under a robust endogenous immune pressure.

Distinct profiles of proliferating CD8+/TCF1+ T cells and CD163+/PD-L1+ macrophages predict risk of relapse differently among treatment-naïve breast cancer subtypes

“…6 ). These findings come in line with a previous study showing a similar association between CD8 + and CD163 + cell densities in breast cancer patients, even though the limited number of TNBC patients precluded a definitive discrimination among the different breast cancer subtypes [ 23 ]. Similarly, PD-L1 status was significantly increased in TNBC and HER2 + versus luminal type A tumors (Fig.…”

“…Prompted by a recent study showing a direct correlation between CD8 + and CD163 + in breast cancer patients [ 23 ], we observed that increased CD8 + , CD8 + Ki67 +, and CD8 + TCF1 + density was associated with high PD-L1 score, CD163 +, and infiltration by CD163 + PD-L1 + cells, irrespective of the breast cancer subtype (Fig. 6 a, b, c and Supplementary Fig.…”

“…Increased CD163 + infiltration is associated in most studies with dismal prognosis in breast cancer patients [ 20 , 21 ], although there is no consistency on the prognostic impact of CD163 + density among different breast cancer subtypes [ 22 ]. Interestingly, it was recently demonstrated that high CD8 + cytotoxic T cell density is associated with high CD163 + TAMs in invasive breast cancer patients suggesting an immune-intrinsic negative feedback mechanism [ 23 ].…”

Modulation of the tumor microenvironment and mechanism of immunotherapy-based drug resistance in breast cancer

“…The tumors also exhibit endogenous immune response-mediated acquired immune resistance (AIR). Endogenous immune response-mediated AIR in tumors hinders the antitumor immune response and impacts overall survival rates by CD8 + cell-induced expression of CD163 and/or FoxP3 [ 231 ]. These data suggested a direct correlation between densities of CD8 + cells with CD163 + and FoxP3 + cells in the breast cancer patients’ specimens.…”

Biomarkers in the Era of Precision Oncology

“…However, given the participation of RAGE in the early steps of the regulation of MDSCs’ development, its therapeutic targeting (also combined with HMGB1 and/or S100A8/A9 targeting) may significantly downregulate their suppressor function. Another AIR mechanism was described by my colleagues and myself [ 22 ]. Namely, we could show a direct correlation between the densities of cells with a cytotoxic effector phenotype (i.e., CD8+ cells) and densities of cells displaying suppressor phenotypes (i.e., CD163+ and FoxP3+ cells) in the primary tumors of patients with breast cancer.…”