Intratumoral cytokines and tumor cell biology determine spontaneous breast cancer-specific immune responses and their correlation to prognosis.
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.
Department of Obstetrics and Gynecology, University Hospital of Heidelberg, Heidelberg, Germany.
Christoph
C
Domschke
Florian
F
Schuetz
Yingzi
Y
Ge
Tobias
T
Seibel
Christine
C
Falk
Benedikt
B
Brors
Israel
I
Vlodavsky
Nora
N
Sommerfeldt
Hans-Peter
HP
Sinn
Marie-Christine
MC
Kühnle
Andreas
A
Schneeweiss
Alexander
A
Scharf
Christof
C
Sohn
Volker
V
Schirrmacher
Gerhard
G
Moldenhauer
Frank
F
Momburg
Philipp
P
Beckhove
D001853:Bone Marrow / Q000276:immunology*; D001940:Breast / Q000276:immunology / Q000378:metabolism; D001943:Breast Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D016022:Case-Control Studies; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008875:Middle Aged; D018396:Mucin-1 / Q000276:immunology / Q000378:metabolism; D011379:Prognosis; D015996:Survival Rate; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016207:Cytokines; D018396:Mucin-1; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma