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01.12.2018 | Research article | Ausgabe 1/2018 Open Access

BMC Cancer 1/2018

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

Zeitschrift:
BMC Cancer > Ausgabe 1/2018
Autoren:
David A. Bernal-Estévez, Oscar García, Ramiro Sánchez, Carlos A. Parra-López
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12885-017-3982-1) contains supplementary material, which is available to authorized users.

Abstract

Background

Vaccination of mice with tumors treated with Doxorubicin promotes a T cell immunity that relies on dendritic cell (DC) activation and is responsible for tumor control in vaccinated animals. Despite Doxorubicin in combination with Cyclophosphamide (A/C) is widely used to treat breast cancer patients, the stimulating effect of A/C on T and APC compartments and its correlation with patient’s clinical response remains to be proved.

Methods

In this prospective study, we designed an in vitro system to monitor various immunological readouts in PBMCs obtained from a total of 17 breast cancer patients before, and after neoadjuvant anti-tumor therapy with A/C.

Results

The results show that before treatment, T cells and DCs, exhibit a marked unresponsiveness to in vitro stimulus: whereas T cells exhibit poor TCR internalization and limited expression of CD154 in response to anti-CD3/CD28/CD2 stimulation, DCs secrete low levels of IL-12p70 and limited CD83 expression in response to pro-inflammatory cytokines. Notably, after treatment the responsiveness of T and APC compartments was recovered, and furthermore, this recovery correlated with patients’ residual cancer burden stage.

Conclusions

Our results let us to argue that the model used here to monitor the T and APC compartments is suitable to survey the recovery of immune surveillance and to predict tumor response during A/C chemotherapy.
Zusatzmaterial
Additional file 1: Table S1. Variables selected for PCA. (DOCX 39 kb)
12885_2017_3982_MOESM1_ESM.docx
Additional file 2: Figure S1. Unresponsiveness of T cell and APC compartments are correlated in BC patients. (A) Principal component analysis (PCA) of several immunological readouts (Additional file  1: Table S1) selected after Varimax rotation, and two principal components (PC) were extracted and show the variable loadings of rotated component matrix, and (B) dot plot of PC score of HD (half-filled circles), and patients before (white box) and after (black box) neoadjuvant chemotherapy. The dashed line represents an axis that separates BC patients from HD. KMO and Bartlett’s Test 0.681 p = 0.005. (C) Receiver operating characteristic (ROC) curves, to differentiate HD vs. BC patients before therapy using TCR internalization by MFI CD3 (left curve, AUC 0.67 p = 0.05). (TIFF 1302 kb)
Additional file 3: Table S2. Association between immunological readouts in peripheral blood and clinicopathologic factors of BC patients. (DOCX 81 kb)
12885_2017_3982_MOESM3_ESM.docx
Additional file 4: Figure S2. Immunomonitoring model of breast cancer patients treated with chemotherapy with A/C. (A) In patients with established BC, the immune system could not control the tumor growth phase called immune escape. Tumor cells exhibit a decreased amount of MHC class I and release suppressive cytokines such as IL-10 and TGF-β, there is a greater frequency of suppressor cells like MDSCs (that secrete arginase), Tregs, and plasmacytoid DCs or immature DCs (with high levels of IDO). These suppressor cells favor a weak cytotoxic T cells activation and inhibition of function of T helper CD4+ cells by suppressive cytokines such as IL-10. (B) In BC patients who are treated with chemotherapy A/C, the proposed immunomonitoring system can evaluate the restoration of immunosurveillance of tumors by promoting the immune response by inducing ICD in tumor cells with the release of DAMPs (CRT, HMGB1, and ATP) and apoptotic bodies that are recognized by immature DCs. This recognition induces maturation of DCs with increased expression of CD80, CD83, CD86, and antigen cross-presentation favoring the recognition of these antigens by T cells. Stimulated T cells induce the production of IL-12 by the interaction CD154 with the CD40 receptor on APCs and thus assisting in the production of IFN-γ providing helper activity to CTLs to attack the remaining tumor cells. (TIFF 6599 kb)
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Literatur
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