Intratumoral Cytokines and Tumor Cell Biology Determine Spontaneous Breast Cancer–Specific Immune Responses and Their Correlation to Prognosis

Abstract

Spontaneous immune responses in cancer patients have been described. Yet their clinical relevance and the conditions for their generation remain unclear. We characterized conditions that determine immune responses in primary breast cancer patients. We used tetramer analysis, ex vivo IFN-γ ELISPOT, cytotoxicity assays, and ELISA in 207 untreated patients and 12 Her-2/neu-specific CD8 T-cell lines to evaluate tumorspecific T cells (TC) in the bone marrow or MUC1-specific antibodies in the blood. Multiplex analysis was performed to quantify 27 intratumoral cytokines, chemokines, and growth factors. Results were compared with multiple pathologic and clinical parameters of the patients and tumors. Forty percent of the patients showed tumor-specific TC responses. These correlated with tumors of high differentiation, estrogen receptor expression, and low proliferative activity, and with a reduced cancer mortality risk. High tumor cell differentiation correlated with increased intratumoral, but not plasma, concentrations of IFN-α and reduced transforming growth factor (TGF)β1. In an in vitro priming experiment these two cytokines increased or inhibited, respectively, the capacity of dendritic cells to induce tumor-reactive TC. Tumor-specific B-cell responses, mainly of IgM isotype, were detectable in 50% of the patients and correlated with advanced tumor stage, increased TGFβ1, reduced IFN-α, and absence of TC responses. We show here that different types of immune responses are linked to distinct cytokine microenvironments and correlate with prognosis-relevant differences in tumor pathobiology. These findings shed light on the relation between immune response and cancer prognosis. [Cancer Res 2009;69(21):8420-8]

Quantitative and Functional Alterations of Plasmacytoid Dendritic Cells Contribute to Immune Tolerance in Ovarian Cancer

“…In this context, we showed that cytokines such as TGF-b and TNF-a detected in ovarian tumor derived-supernatants, were involved in this pDC dysfunction. The inhibitory role of TGF-b is consistent with a previous study showing that increased intratumoral IFN-a levels correlates with reduced TGF-b1 in breast cancer patients (33). Moreover, recent reports in mice and human showed that this cytokine contributes to peyer patches, splenic stromal, and tumor environments mediated inhibition of pDC capacity to produce IFN-a (29,34,35).…”

Tumor-specific cytotoxic T lymphocyte activity determines colorectal cancer patient prognosis

“…This suggests that in some CRCs dominant regulatory mechanisms are active, either directing TC responses into other functional polarization, which renders them anergic or exhausted, or inhibiting their functional activity. We indeed found higher concentrations of TNF-α particularly in those tumors that contained lower levels of the TC-suppressive Treg effector cytokine, TGF-β1 (34). Thus, increased intratumoral TNF-α concentrations indicate not only systemic induction of functionally potent CTL responses but also their dominance in situ over a major local immune-suppressive mechanism.…”

“…CD4 + and CD8 + TILs from CRCs that rested overnight without stimulation showed no expression of TNF-α, while subsequent polyclonal activation with anti-CD3/anti-CD28 antibodies caused marked TNF-α expression in CD8 + and CD4 + TILs ( Figure 1, A and B) and also in freshly isolated blood-derived TCs from 5 patients with CRC ( Figure 1C). Altogether, activation-induced TNF-α expression was lower in TILs than in peripheral bloodderived TCs (PBTCs) from the patients -most likely reflecting the exhausted state of intratumoral TCs (34). Taken together, TNF-α expression in TILs is restricted to a population of activated TCs.…”

“…Altogether, we detected tumor-reactive TCs in 44% of the patients ( Figure 2B). The detection rate was not influenced by differences in IFN-γ background activity in the control wells, as these did not differ between tumor-reactive and unresponsive test samples (15,34). the respective tumor vasculature (18,19).…”

Prognostic Significance of Peripheral Blood Flow Cytometry Parameters in Patients with Non-Metastatic Breast Cancer

“…However, we need to define new prognostic tools and develop highly targeted therapies (Emens et al, 2004). Immune functions and their relation to prognosis in cancer patients is an area of great interest for many researchers in recent years (Domschke et al, 2009). A study revealed that the preoperative expression levels of cluster of differentiation (CD) of the CD3+, CD4+/CD8+ and NK+ cells in patients with colorectal cancer was positively correlated with prognosis (Wang et al, 1999).…”