Lymph node invasion by tumor cells modifies the distribution and phenotype of dendritic and T cell subsets in breast cancer patients.

NÚÑEZ NICOLAS GONZALO; NADAN A.T; SEGURA E; PÉROL L; MILDER M; VIEL S; DE LA ROCHERE P; LOIRAT D; MESEURE D; AMZALLAG N; SASTRE-GARAU X; SEDLIK C; AMIGORENA S; PIAGGIO E

Congreso; 13th CIMT ANNUAL MEETING; 2015

In human breast cancer the invasion of tumor-drain- ing lymph nodes (TDLNs) contributes to disease pro- gression and has predictive value. TDLNs dendritic cells (DCs) present tumor antigens to naïve T cells and induce their polarization into different function- al subsets (Th1, Th2, regulatory T cells (Treg) ...) leading to antitumor T cell responses or to tolerance. Here, we compared the immune profile of 70 untreat- ed breast cancer Invaded (INV) versus Non-invaded (NI) TDLNs, with the aim to identify immunomod- ulatory mechanisms associated with the presence of the metastatic tumor cells. We studied by multi-col- or flow cytometry the distribution of 6 different DC subpopulations and observed in INV TDLNs a significant decrease in the percentage of BDCA1+ DCs (P < 0.05) and a significant increase in the per- centage of CD11c+HLADR+CD14+ cells (P < 0.01), including macrophages and inflammatory DCs, com- pared to NI TDLNs (P < 0.05). Interestingly, in vitro, these CD14+ myeloid cells induced the expression of FoxP3 in proliferating CD4+ T cells, suggesting a suppressive role. We also found a significant lower frequency of naïve conventional and Treg cells in INVTDLNs (P < 0.05). Both, in NI and INV TDLNs, memory conventional and Treg cells were highly po- larized, mainly to the Th1, but also to the Th2, Th17, Tfh and Th22 phenotypes, as determined by chemo- kine receptor and transcription factor expression. Further functional analysis showed that after ex-vivo PMA/Iono stimulation, the CD4+ and CD8+ T cells, but not the Tregs produced high amounts of IFN-γ,being the IFN-γ production significantly higher in INV TDLNs (P < 0.05). Overall, we observed that immune cells with tolerogenic potential (Tregs, mac- rophages) and effector CD4+ and CD8+ T cells from metastatic TDLNs, both show evidence of high acti- vation. These results potentially explain the power ofimmunotherapies targeting the former ones that unleash the anti-tumor activity of the highly activat- ed effector T cells.