Abstract:
Breast cancer cells exploit the up-regulation or down-regulation of immune checkpoint
proteins to evade anti-tumor immune responses. To explore the possible involvement of
this mechanism in promoting systemic immunosuppression, the pre-treatment levels of
soluble co-inhibitory and co-stimulatory immune checkpoint molecules, as well as those
of cytokines, chemokines, and growth factors were measured in 98 newly diagnosed
breast cancer patients and compared with those of 45 healthy controls using multiplex
bead array and ELISA technologies. Plasma concentrations of the co-stimulatory immune
checkpoints, GITR, GITRL, CD27, CD28, CD40, CD80, CD86 and ICOS, as well as the
co-inhibitory molecules, PD-L1, CTLA-4 and TIM-3, were all significantly lower in early
breast cancer patients compared to healthy controls, as were those of HVEM and sTLR-2,
whereas the plasma concentrations of CX3CL1 (fractalkine), CCL5 (RANTES) and those
of the growth factors, M-CSF, FGF-21 and GDF-15 were significantly increased.
However, when analyzed according to the patients’ breast cancer characteristics, these
being triple negative breast cancer (TNBC) vs. non-TNBC, tumor size, stage, nodal status
and age, no significant differences were detected between the plasma levels of the various
immune checkpoint molecules, cytokines, chemokines and growth factors. Additionally,
none of these biomarkers correlated with pathological complete response. This study has
identified low plasma levels of soluble co-stimulatory and co-inhibitory immune checkpoint
molecules in newly diagnosed, non-metastatic breast cancer patients compared to
healthy controls, which is a novel finding seemingly consistent with a state of systemic
immune dysregulation. Plausible mechanisms include an association with elevated levels
of M-CSF and CCL5, implicating the involvement of immune suppressor cells of the M2-macrophage/monocyte phenotype as possible drivers of this state of systemic
immune quiescence/dysregulation.
