Tumor-dependent down-regulation of the ζ-chain in T-cells is detectable in early breast cancer and correlates with immune cell function.

Suppressive factors produced by tumors or tumor-associated cells represent a major obstacle to immune-mediated tumor eradication and immunotherapy. We studied tumor-dependent changes in expression of the ζ-chain, a key molecule for the transduction of stimulatory signals through the T-cell receptor and activating receptors on natural killer (NK) cells, in patients with early (stages 1 and 2) breast cancer. Ex-vivo levels of ζ-chain expression, proliferation and cytokine expression in lymphocyte subpopulations were measured in breast tumors, their draining lymph nodes and in pre- and postoperative blood samples of cancer patients and healthy controls by multi-parametric flow cytometry. We found that T-cell ζ-chain expression in peripheral blood of breast cancer patients (n = 29) was down-regulated compared with healthy controls (n = 10) (p ≤ 0.033), which was most pronounced in stage 2 (n = 15, p ≤ 0.004). T- and NK-cell ζ-chain loss was most distinct in the tumor and decreased with increasing distance (p ≤ 0.015). After surgical tumor resection, peripheral blood ζ-chain levels normalized to those observed in healthy controls. ζ-chain expression in peripheral blood T-cells correlated with lymphocytic proliferative activity (p ≤ 0.035), and with the expression of proinflammatory cytokines in CD8+ T-cells (p ≤ 0.035). Breast cancer patients had lower numbers of circulating early memory CD8+ T-cells than healthy donors (p ≤ 0.000), correlating with lower T-cell ζ-chain levels (p ≤ 0.011). Our findings suggest that phenotypic and functional alterations in lymphocytes can be detected even in early stage breast cancer patients. The observed immunosuppression appears to be systemic and tumor dependent, as it is strongest in the tumor, correlates with tumor stage and normalizes after surgery.