Cognate Nonlytic Interactions between CD8+ T Cells and Breast Cancer Cells Induce Cancer Stem Cell-like Properties.

Targeting of tumor immune escape mechanisms holds enormous therapeutic potential. Still, most patients progress under immune checkpoint blockade and some even become hyperprogressors. To investigate how cancer cells respond to activated but ineffective T cells, we challenged peptide-loaded MCF-7 breast cancer cells with antigen-specific CD8+ T cells in which lytic granules had been destroyed by pretreatment with Concanamycin A. Gene expression analysis after coculture revealed simultaneous induction of PD-L1, IDO1, CEACAM1, and further immunoregulatory checkpoints in breast cancer cells. Strikingly, we further observed gene signatures characteristic for dedifferentiation and acquisition of pluripotency markers including Yamanaka factors. Cognate interaction with nonlytic CD8+ T cells also increased the proportion of stem cell-like cancer cells in a cell-to-cell contact- or (at least) proximity-dependent manner in various cell lines and in primary breast cancer cell cultures; this induction of stem cell-like properties was confirmed by enhanced tumor-forming capacity in immunodeficient mice. Resulting tumors were characterized by enhanced cell density, higher proliferation rates, and increased propensity for lymphoid metastasis. These findings describe a widely underappreciated pathway for immune escape, namely immune-mediated dedifferentiation of breast cancer cells, which is associated with profound changes in gene expression and cellular behavior. As the enhanced malignant potential of cancer cells after nonlytic cognate interactions with CD8+ T cells enables increased tumor growth and metastasis in BALB/cnu/nu mice, the described mechanism may provide a possible explanation for the clinical phenomenon of hyperprogression in response to unsuccessful immunotherapy. SIGNIFICANCE: This study shows that ineffective immune responses not only fail to clear a malignancy, but can also activate pathways in cancer cells that promote stemness and tumor-seeding capacity.

Implementation of a Systematic Literature Search Strategy in a National Breast Cancer Guideline: The Relevance of Systemic Therapy in Lymph Node Recurrent Disease.

PURPOSE: Our aim was to implement a structured literature search using PICO (patient/intervention/comparison/outcome) questions and a standardized consensus method for the German Guideline 'Detection, diagnostics, therapy and follow-up of Breast Cancer' using, as an example, the significance of systemic therapy in lymph node recurrent disease (LNRD). METHODS: We defined specified PICO questions according to the clinical significance of a recommendation for systemic therapies in locoregional LNRD. A methodologist performed a systematic literature search including randomized controlled trials, systematic reviews and observational studies (2007-2016). In a consensus conference, the level of evidence and consensus was determined and the clinical recommendation was adopted. RESULTS: In total 143 publications were identified according to the search strategy including 14 duplicates, which were excluded. 4 publications were included based on experts' choice. The team excluded 119 publications, leaving 14 that were then screened by a full text search. Finally, 1 publication was found to be of methodologically and clinically reliable content. The conclusion of this publication in favor of systemic therapy for LNRD received strong consent from the consensus conference. CONCLUSIONS: The literature search strategy using PICO questions helped to achieve a fast and standardized selection of publications. The recommendation concerning systemic treatment of LNRD was first implemented in the update of the German Breast Cancer guideline.

Evaluation of Sentinel Lymph Node Biopsy and Axillary Lymph Node Dissection for Breast Cancer Treatment Concepts - a Retrospective Study of 1,214 Breast Cancer Patients.

BACKGROUND: Most breast cancer patients require lumpectomy with axillary sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND). The ACOSOG Z0011-trial failed to detect significant effects of ALND on disease-free and overall survival among patients with limited sentinel lymph node (SLN) metastases. Intense dose-dense chemotherapy and supraclavicular fossa radiation (SFR) are indicated for patients with extensive axillary metastases. In this multicentered study, we investigated the relevance of ALND after positive SLNB to determine adequate adjuvant therapy. METHODS: We retrospectively analyzed data from 1,214 patients with clinically nodal negative T1-T2 invasive breast cancer undergoing surgery at Hanau City Hospital Breast cancer center. RESULTS: 681 patients underwent ALND after SLNB. 20 patients (8.5%) from the group with 1 or 2 SLN metastases (n = 236) showed more than 3 lymph node metastases after ALND. 13 patients (31.7%) from the group with more than 2 SLN metastases (n = 41) were diagnosed with a minimum of 4 axillary lymph node metastases after ALND. CONCLUSIONS: In 8.5% of the patients with 1 or 2 SLN metastases, ALND detected more than 3 macrometastases, setting the indication for intense dose-dense chemotherapy and SFR. More than 2 SLN metastases, T stage and grading predict lymph node metastases.