Chemotherapy and radiation therapy elicits tumor specific T cell responses in a breast cancer patient

Abstract

BackgroundExperimental evidence and clinical studies in breast cancer suggest that some anti-tumor therapy regimens generate stimulation of the immune system that accounts for tumor clinical responses, however, demonstration of the immunostimulatory power of these therapies on cancer patients continues to be a formidable challenge. Here we present experimental evidence from a breast cancer patient with complete clinical response after 7 years, associated with responsiveness of tumor specific T cells.MethodsT cells were obtained before and after anti-tumor therapy from peripheral blood of a 63-years old woman diagnosed with ductal breast cancer (HER2/neu+++, ER-, PR-, HLA-A*02:01) treated with surgery, followed by paclitaxel, trastuzumab (suspended due to cardiac toxicity), and radiotherapy. We obtained a leukapheresis before surgery and after 8 months of treatment. Using in vitro cell cultures stimulated with autologous monocyte-derived dendritic cells (DCs) that produce high levels of IL-12, we characterize by flow cytometry the phenotype of tumor associated antigens (TAAs) HER2/neu and NY-ESO 1 specific T cells. The ex vivo analysis of the TCR-Vβ repertoire of TAA specific T cells in blood and Tumor Infiltrating Lymphocytes (TILs) were performed in order to correlate both repertoires prior and after therapy.ResultsWe evidence a functional recovery of T cell responsiveness to polyclonal stimuli and expansion of TAAs specific CD8+ T cells using peptide pulsed DCs, with an increase of CTLA-4 and memory effector phenotype after anti-tumor therapy. The ex vivo analysis of the TCR-Vβ repertoire of TAA specific T cells in blood and TILs showed that whereas the TCR-Vβ04-02 clonotype is highly expressed in TILs the HER2/neu specific T cells are expressed mainly in blood after therapy, suggesting that this particular TCR was selectively enriched in blood after anti-tumor therapy.ConclusionsOur results show the benefits of anti-tumor therapy in a breast cancer patient with clinical complete response in two ways, by restoring the responsiveness of T cells by increasing the frequency and activation in peripheral blood of tumor specific T cells present in the tumor before therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2625-2) contains supplementary material, which is available to authorized users.

Monitoring the responsiveness of T and antigen presenting cell compartments in breast cancer patients is useful to predict clinical tumor response to neoadjuvant chemotherapy

“…We hypothesized that a favorable clinical response of BC tumors to neoadjuvant therapy with Doxorubicin and Cyclophosphamide (A/C) will revert suppression in these two compartments. In a recent study, we design an in vitro system to monitor the specific anti-tumor response before and after anti-tumor therapy [ 9 ]. Our results suggest that the status of disease-free survival and a complete clinical response is supported by tumor-specific T lymphocytes induced by anti-tumor treatment.…”

PLAC1-specific TCR-engineered T cells mediate antigen-specific antitumor effects in breast cancer

“…A total of 1x10 6 T cells were collected by centrifugation with 650 x g for 10 min at room temperature, fixed with paraformaldehyde for 30 min at room temperature, washed twice with PBS, and then blocked with fluorescence-activated cell sorter (FACS) solution (PBS containing 2% FBS and 0.1% NaN 3 ) for 30 min at 4˚C. Then cells were stained using fluorescein isothiocyanate (FITC)-labeled monoclonal antibody (mAb) against human CD8 (cat.…”

“…Briefly, the mice were pre-treated with 200 µg/kg estradiol valerate (Sigma-Aldrich; Merck KGaA) by gastric perfusion, starting 1 week prior to cell implantation as previously described (24). Subsequently, each of the mice were administered ~5x10 6 MCF-7 cells (in 100 µl serum-free media) mixed with 100 µl Matrigel (BD Biosciences) into the left flank subcutaneously. Protocols for the treatment of nude mice were approved by the Laboratory Animal Ethics Committee of the Medical Laboratory Animal Center of Guangdong Province.…”

“…To examine the in vivo efficacy of PLAC1 TCR-transgenic CD8+ T cells, 5x10 6 MCF-7 cells were inoculated into BALB/c-nu mice to establish a subcutaneous transplant tumor model. Upon achieving a mean tumor volume of 150 mm 3 , the mice were randomly divided into 3 groups (5 animals/group) and subjected to intravenous tail vein transplantation of either normal saline, 1x10 7 PLAC1 TCR-transduced CD8+ T cells or NC-transduced CD8+ T cells, twice with a 1 week interval.…”

“…A total of 882,900 cases were diagnosed and 324,300 mortalities occurred in developing countries in 2012, accounting for 25% of all cancer cases and 15% of all cancer-associated mortalities amongst females (3). Therapeutic treatments for breast cancer typically include surgery, chemotherapy, radiotherapy, endocrine therapy and molecular targeted therapy (4)(5)(6). Although the prognosis for patients with early-stage breast cancer has improved over previous years, the 5-year survival rate of patients with metastatic breast cancer remains <20% in the United States in 2016 (7).…”