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

Christoph Domschke,Yingzi Ge,Benedikt Brors,Volker Schirrmacher,Frank Momburg,Christof Sohn,Christine Falk,Gerhard Moldenhauer,Andreas Schneeweiss,Tobias Seibel,Marie-Christine Kühnle,Alexander Scharf,Hans-Peter Sinn,Nora Sommerfeldt,Florian Schuetz,Israel Vlodavsky,Philipp Beckhove

doi:10.1158/0008-5472.can-09-1627

Christoph Domschke, Yingzi Ge + Show 15 more

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https://doi.org/10.1158/0008-5472.can-09-1627

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Journal: Cancer Research	Publication Date: Oct 28, 2009
Citations: 56	License type: cc-by

Affiliation: Technion – Israel Institute of Technology

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-gamma ELISPOT, cytotoxicity assays, and ELISA in 207 untreated patients and 12 Her-2/neu-specific CD8 T-cell lines to evaluate tumor-specific 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-alpha and reduced transforming growth factor (TGF)beta1. 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 TGFbeta1, reduced IFN-alpha, 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.

Highlights

Spontaneous T-cell (TC) responses are increasingly recognized as beneficial prognostic factors in cancer
Dendritic cells (DC)-pretreatment with neither TGFβ1 nor IFN-α had no effect on memory TC of the same patients. These findings indicate that IFN-α and TGFβ1 are present in breast carcinomas at sufficient amounts to regulate the capacity of immature DC (iDC) to induce primary TA-specific TC
TC immunity was determined by the presence of IFN-α together with low concentrations of TGFβ1, whereas humoral immune responses were generated in the absence of intratumoral IFNα together with increased TGFβ1

Summary

Introduction

Spontaneous T-cell (TC) responses are increasingly recognized as beneficial prognostic factors in cancer. Increased TC infiltration is a major prognostic factor in colorectal cancer and. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). We here used the repertoire of TC in the BM of primary untreated, nonmetastasized breast cancer patients to characterize features of patients or their tumors that are associated with the spontaneous generation of TA-specific immune responses and to evaluate their potential prognostic implications

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