Presence of circulating Her-2 reactive CD8 T cells is associated with a lower frequency of MDSCs and better survival in elderly breast cancer patients

Abstract

Breast cancer is one of the most common cancers among women. The risk of breast cancer has increased dramatically recently and a higher number of elderly women are being diagnosed with the disease. Myeloid-derived suppressor cells (MDSCs) have been implicated in breast cancer prognosis. Their frequency has been associated with tumour burden and studies have shown a poor prognosis in cases of metastatic breast cancer. MDSCs are known to impair the proliferation of T cells and to promote T cell apoptosis. Associations between MDSC levels and immune responses of the host to tumour-associated antigens had not been investigated. Here, we have studied T cell responses to Her-2 antigens, as well as the frequency of Tregs and MDSCs, in 40 untreated breast cancer patients (65-87 years of age) at diagnosis. After a 12-day in vitro expansion of memory cells stimulated by Her-2-derived peptides, CD4+ T cells reactive to Her-2 were detected in 84% of patients by intracytoplasmic staining simultaneously for TNF, IFN-γ, IL-2, IL-5, IL-10 and IL-17. In contrast, only 47% of patients had Her-2-reactive CD8+ T cells. The patients who lacked a CD8 response tended to have higher frequencies of Lineage(neg) CD14+ HLA-DR(neg) cells (p = 0.09). Importantly, the 5-year survival rate of patients who mounted a CD8+ T cell response and had a lower frequency of this particular subset of MDSC was 100% compared to only 53% in patients without Her-2-reactive CD8+ T cells and with higher frequencies of MDSCs (p = 0.03). This survival advantage was also observed in non-metastatic patients, with only a 38% 5-year survival in patients without a CD8 response and high levels of MDSCs compared to 100% survival of those who had a CD8 response and a lower frequency of MDSCs (p = 0.016). Similarly, for Tregs, patients who lacked a CD8 response to Her-2 and had higher frequencies of CD4+ Foxp3+ CD127(low) CD25+ Tregs had only 50% survival when compared to the 100% survival of the patients who mounted a CD8 response and had lower frequency of Tregs (p = 0.03). Also, for activated CD4+ CD45RA(neg)Foxp3(hi) Tregs, a similar trend was observed with 57% survival in patients who lacked a CD8 response and had higher frequencies of activated Tregs compared to the 100% survival in patients with a CD8 response and lower frequencies of activated Tregs (p = 0.06). Our data thus demonstrate a negative role of MDSCs and Tregs in prognosis of breast cancer patients, which might be through dampening favorable immune responses to tumour-associated antigens.