Anti-Tumor Immunity to Patient-Derived Breast Cancer Cells by Vaccination with Interferon-Alpha-Conditioned Dendritic Cells (IFN-DC)
<p>Phenotypic and functional analysis of peripheral blood lymphocytes (PBL) stimulated with HOCl-oxidized MCF-7 breast tumor cell lysate. (<b>a</b>) Dot-plot analysis of CD4+ and CD8+ cells as determined by flow cytometry in PBL stimulated with IFN-DC. PBL isolated from HLA-A2+ healthy blood donors were cultured with autologous IFN-DC (IFN-DC/PBL ratio of 1:4) pulsed with MCF-7 tumor cell lysate, as described in <a href="#sec2-vaccines-12-01058" class="html-sec">Section 2</a>. Representative results of three independent experiments are shown. (<b>b</b>) Cytokine production (IFN-γ, TNF-α and IL-10) in culture supernatants as evaluated by ELISA on days 7 and 14 of co-culture. (<b>c</b>) Degranulation assay as a surrogate evaluation of cytotoxic activity by detection of CD107a membrane expression and intracellular IFN-γ production in CD8+ and natural killer (NK) cells. Representative dot-plot analysis in electronically gated CD8+CD3+ and CD56+CD3- cells in PBL co-cultured with tumor cell-loaded IFN-DC. On day 21 of culture, PBL were restimulated with MCF-7 or K562 target cell lines for 4 h at 37 °C (E:T ratio of 2:1) (see <a href="#sec2-vaccines-12-01058" class="html-sec">Section 2</a>). Dot-plots show CD107a membrane exposure and IFN-γ expression in electronically gated CD8+CD3+ and CD56+CD3- lymphocytes in response to the indicated target cells. Results from one representative experiment out of four are shown. (<b>d</b>) Representative cytotoxicity assay against NK-sensitive K562 and MCF-7 target cell lines as evaluated by a Calcein-AM assay (see <a href="#sec2-vaccines-12-01058" class="html-sec">Section 2</a>) at different E:T ratios. Data are mean ± SD of a triplicate assay of PBL derived from an HLA-A2+ donor.</p> "> Figure 2
<p>Evaluation of tumor-growth inhibition by in vivo immunization of hu-PBL-NSG mice with IFN-DC loaded with HOCl-oxidized tumor cell lysate. (<b>a</b>) Vaccination schedule. Mice were reconstituted with HLA-A2+ PBL as soon as the implanted tumors became detectable by in vivo bioluminescence imaging (10–11 days). Humanized mice were then randomized into treatment and control groups. (<b>b</b>) Quantitative evaluation of tumor cell growth by bioluminescence analysis. Tumor burden was detected by in vivo non-invasive imaging of the firefly luciferase expressing MCF-7 cells after intraperitoneal luciferin injection. Tumor bioluminescence intensity was plotted in pseudocolor over black/white photographs and quantified as total flux in photons/seconds. Graph represents mean total flux of MCF-7 cell growth rate in hu-PBL-NSG mice immunized as described. The data are presented as mean ± SEM. The difference in tumor growth was highly statistically significant only at the last time point, day 47 (** <span class="html-italic">p</span> < 0.01 by Mann–Whitney test). (<b>c</b>) Representative tumor burden images of the two groups (CTR vs. vaccine) at different time points by IVIS imaging system. (<b>d</b>) Evaluation of IFN-γ levels in mouse sera collected at the time of sacrifice.</p> "> Figure 3
<p>Isolation and characterization of patient-derived breast cancer organoids (PDBCOs). (<b>a</b>) Representative bright-field images of 5 PDBCOs used for the study, showing different structures: cohesive and discohesive organoids, dense and solid (PBR-13, PBR-14, PBR-16, PBR-17), cohesive organoids, cystic and grape-like (P-BR-22). Scale bar, 100 µm. (<b>b</b>) Comparative histological and immunohistochemical images of BC tissues and derived organoid lines. Shown are representative examples of H&E staining and IHC of either HR or HER-2 status for PBR-17. Scale bar, 200 µm. (<b>c</b>) Stacked bar chart indicating the percentage of PDBCO lines found positive (grey) and negative (black) by IHC for the receptor expression grouped per original tumor receptor status. (<b>d</b>) Bar graph displaying proliferation rate percentage of PDBCOs and corresponding parental tumors as quantified by Ki67 immunohistochemical staining. (<b>e</b>) Representative dot-plot graphs showing CK14 and CK8-18 expression in PBR-13, PBR-16 and PBR-22 (<b>f</b>) CLSM analyses of PFA-fixed PDBCOs stained for CK8-18, SMA and E-cadherin (green); 4′-6-Diamidino-2-phenylindole (DAPI) was used to counterstain nuclei (light blue). Several (>50 organoids) were observed for each condition and representative images are shown. Scale bars, 10 µm.</p> "> Figure 4
<p>Isolation and characterization of breast cancer patient-derived metastatic cells (PDMCs). (<b>a</b>) Representative phase-contrast images of PDMCs from ascitic fluid (MBR-1, MBR-2) or pleural effusion (MBR-3, MBR-4) cultured in serum-free conditions. Scale bar, 100 µm. (<b>b</b>) CLSM analyses of PFA-fixed PDMCs stained for E-cadherin, vimentin Taz and beta-catenin (green); DAPI was used to counterstain nuclei (light blue). Several fields were observed for each condition and representative images are shown. Scale bars, 10 µm. (<b>c</b>) Dot-plots showing luminal CK8-18 and myoepithelial CK14 expression in PDMC lines. (<b>d</b>) Bar chart reporting percentages of CD44<sup>high</sup>CD24<sup>−/low</sup> phenotype in MBR-1, MBR-2, MBR-3 and MBR-4 lines obtained from ascitic fluid or pleural effusion of breast cancer metastatic patients. Percentages, referring to CD44<sup>high</sup>CD24<sup>−/low</sup> positive cells, were determined by setting the gate on the isotype control from at least two independent FACS stainings.</p> "> Figure 5
<p>Characterization of PBL cultures from breast tumor patients stimulated with IFN-DC loaded with HOCl-oxidized autologous tumor cell lysate. (<b>a</b>). Representative phenotypical analysis of IFN-DC obtained from breast tumor patients. IFN-DC were differentiated from peripheral blood monocytes as described in <a href="#sec2-vaccines-12-01058" class="html-sec">Section 2</a>. Partially mature CD11c+ IFN-DC ex-pressed high levels of the costimulatory molecules CD80 and CD86, as well as variable levels of the maturation marker CD83. (<b>b</b>) IL-12 release in supernatants collected from IFN-DC cultures on day 3 of differentiation. (<b>c</b>) Representative phenotypic analysis of PBL isolated from breast tumor patients and cultured with autologous IFN-DC loaded with HOCl-oxidized tumor cell lysate for 14 days. (<b>d</b>) Evaluation of CD4, CD8 and NK cell percentages in PBL from breast cancer patients before (T0) and after 14 days of culture (T14) with autologous IFN-DC. (<b>e</b>) Flow cytometric analysis of CD4 and CD8 cell memory subsets of freshly purified PBL from breast cancer patients and after 14 days of culture with autologous IFN-DC loaded with HOCl-oxidized tumor cell lysate. (<b>f</b>) Cytokine release (IFN-γ, TNF-α and IL-10) in culture supernatants as evaluated by ELISA on day 14 of co-cultures.</p> "> Figure 6
<p>Antitumor activity of PBL from breast cancer patients co-cultured with IFN-DC loaded with HOCl-oxidized autologous tumor cell lysate. PBL isolated from nine patient blood donors were cultured with IFN-DC pulsed with HOCl-oxidized tumor cell lysate for 14 days. (<b>a</b>) Degranulation activity of expanded effectors cells tested against autologous breast cancer target cells as detected by flow cytometry; analysis of CD107a membrane expression and intracellular IFN-γ. (<b>b</b>) Representative degranulation assay as assessed by dot-plot analysis of ectopic CD107a and IFN-γ expression in CD8+ and CD3-CD56+ NK cells derived from three representative breast cancer patients in response to autologous tumor cells. (<b>c</b>) Cytotoxic assay of PBL culture from breast cancer patients after in vitro culture for 14 days, tested against autologous breast cancer cells. (<b>d</b>) Phenotypic analysis of CD8 cells from patient PBR-22 (HLA-A2+) stimulated with IFN-DC loaded with HOCl-oxidized autologous tumor cell lysate for 14 days. (<b>e</b>) Cytotoxic activity of PBL from PBR-22 (HLA-A2+) as compared to PBR-13 (HLA-A2–) as determined by cytotoxic assay towards HLA-A2+ MCF-7 target cells. (<b>f</b>) Degranulation activity as determined by dot plot analysis of CD107a and IFN-γ expression in CD8+ and CD3-CD56+ NK cells from patients PBR-22 and P-BR13 toward MCF-7 target cells.</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients and Samples
2.2. Statistical Analysis
2.3. Cell Lines
2.4. Cell Preparation
2.5. Isolation of Patient-Derived BC Organoids (PDBCOs) from Primary Tumors
2.6. Isolation of Patient-Derived Metastatic (PDM) Cells from Ascitic Fluid or Pleural Effusion
2.7. Confocal Laser Scanning Microscopy (CLSM)
2.8. Flow Cytometry
2.9. Immunohistochemistry
2.10. Lysate Tumor Cell and PBL/DC Cocultures
2.11. Therapeutic Vaccination of Tumor-Bearing Hu-PBL-NSG Mice
2.12. Cytokine Assay
2.13. Cytotoxicity Assay
3. Results
3.1. In Vitro Induction of Immune Responses to MCF-7 Breast Tumor Cells
3.2. In Vivo Efficacy of Therapeutic Vaccination with IFN-DC Loaded with HOCl-Oxidized Tumor Cell Lysate
3.3. Patient-Specific BC Organoids Allow an Efficient Expansion of BC Cells and a Faithful Reconstruction of Parental Tumors Maintaining Antigenic Profiles
3.4. In Vitro Evaluation of the IFN-DC-Based Vaccine in a Selected Group of Breast Cancer Patients
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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(a) | |||||||||
Patient No. | Age | Menopausal Status | Histology | Pathology, Tumor Size (pT) | Lymph Node Status (pN) | Grade | ER/PgR/HER2 2 Status (%) | Ki67 (%) | Neo-Adjuvant Treatment and Response |
1 | 37 | Pre | IDC nos 1 | T2 | SN neg | 3 | -/-/- | 70 | NA 3 |
2 | 69 | Post | ILC | T1b(m) | N2a | X 4 | 95/1/- | 5 | Ctx-Epi + Txl(RP) |
3 | 46 | Pre | NET | T2 | N1(sn) | 3 | 80/80/- | 70 | NA |
4 | 34 | Pre | IDC | T2ypM1(L) | N1a | 3 | -/-/- | 60 | Beva + Txl (RP-Li; PD-T) |
5 | 52 | Post | IDC | T2 | N1(mi) | 2 | 90/2/- | 30 | NA |
6 | 73 | Post | IDC | T2 | N0(sn) | 2 | 90/3/- | 25 | NA |
7 | 75 | post | IDC nos | T1c | N1mi(sn) | 2 | 95/95/- | 20 | NA |
8 | 82 | Post | IDC | T3 | N0(sn) | 2 | 95/95/- | 20 | NA |
9 | 49 | Pre | R 5:IDC | T2 | N0(sn) | 2 | 95/95/- | 30 | NA |
L: ILC | T2m | N1(sn) | 2 | 95/95/- | 15 | ||||
10 | 62 | Post | IDC | T1c | N1mi(sn) | 2 | 95/95/- | 20 | NA |
11 | 43 | Pre | IDC | T1c | N1a | 2 | 95/95/- | 20 | NA |
12 | 46 | Pre | IDC nos | T2 | N0(sn) | 2 | 95/95/- | 20 | NA |
13 | 49 | Pre | IDC nos | T1c | N1a | 2 | 90/90/- | 10 | NA |
14 | 51 | Pre | Ca papillary + NET | T2 | N1(sn) | 2 | 95/85/- | 20 | NA |
15 | 66 | Post | IDC | T2 | N0(sn) | 3 | 10/-/- | 50 | NA |
16 | 50 | Pre | ILC + NET | T3 | N1a | 3 | 90/90/- | 50 | NA |
17 | 32 | Pre | IDC apocrine | T2(m) | N1a | 3 | 80/-/- | 30 | NA |
18 | 76 | Post | IDC | T1c(m) | N3a | 3 | -/-/- | 25 | NA |
19 | 41 | Pre | IDC | T2 | N0 | 3 | -/-/- | 80 | Epi + Taxol(PD) |
20 | 78 | Post | IDC nos | T2 | N1mi(sn) | 2 | 95/70/- | 15 | NA |
21 | 79 | Post | IDC nos | T2(m) | N1a | 2 | 95/-/- | 22 | NA |
22 | 77 | Post | ILC | T2 | N1a | 2 | 90/40/- | 25 | NA |
1 IDC, infiltrating ductal carcinoma; DCIS, ductal carcinoma in situ; ILC, invasive lobular carcinoma; ILCI, lobular carcinoma in situ, Neuroendocrine tumor (NET); sn (sentinel lymph node); mi (micrometastasis); 2 ER, estrogen receptor; PgR, progesterone receptor, expressed in percentage; HER2status + positive or—negative; 3 NA, not applicable; Ctx: cyclophosphamide; Epi, epirubicin; Beva, bevacizumab; Txl: taxol; FEC, 5-fluorouracil, Epi, epirubicin, Ctx, cyclophoasphamide; 4 X, undetermined; 5 R: right side; L: left side. | |||||||||
(b) | |||||||||
Patient No. | Age | Source of Cells | Histology on Original T | Pathology, pTNM Original T | Grade | ER/PgR/HER2 2 Status of the Original T (%) | ER/PgR/HER2 Status of M Disease | Previous Treatments | |
1 | 50 | Ascites | ILC 1 | NA 3 | NA | 95/95/+ | -/-/- | 5 CMF, Herc, Tam, AI, Pertuzumab, Dxt, CDDP, Gem | |
2 | 59 | Ascites | DCIS+ comedoCa | pT1mN0 (m) | 3 | 70/60/- | -/-/- | Fulvestrant, Everolimus, Exem; Txl | |
3 | 67 | PE 6 | IDC | T3N+ | 3 | 95/30/- | -/-/- | NA (met at the diagnosis) | |
4 | 43 | PE | IDC | pT1cN1a | 2 | 80/50/+ | -/-/- | FEC, Herc, Cape, Lapatinb, Txl, CBDCA, CMF | |
1 IDC, infiltrating ductal carcinoma; DCIS, ductal carcinoma in situ; ILC, invasive lobular carcinoma; ILCI, lobular carcinoma in situ comedoca, comedocarcinoma; Neuroendocrine tumor (NET); sn (sentinel lymph node); mi (micrometastasis); 2 ER, estrogen receptor; PgR, progesterone receptor, expressed in percentage; HER2status + positive or—negative; 3 NA, not applicable; Ctx: cyclophosphamide; Epi, epirubicin; Beva, bevacizumab; Txl: taxol; FEC, 5-fluorouracil, Epi, epirubicin, Ctx, cyclophoasphamide; 4 X, undetermined; 5 R: right side; L: left side1 5 CMF, cyclophosphamide, methotrexate, 5-fluorouracil; Herc, Herceptin; Tam, Tamoxifen; A.I.: aromatase inhibitors; Exeme, exemestane; Dxt, Docetaxel; CDDP, Cisplatino; GEM, gemcitabine; Txl, Taxol; Cape: capecitabina; CBDCA: carboplatino; 6 PE: pleural effusion. |
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Lapenta, C.; Santini, S.M.; Antonacci, C.; Donati, S.; Cecchetti, S.; Frittelli, P.; Catalano, P.; Urbani, F.; Macchia, I.; Spada, M.; et al. Anti-Tumor Immunity to Patient-Derived Breast Cancer Cells by Vaccination with Interferon-Alpha-Conditioned Dendritic Cells (IFN-DC). Vaccines 2024, 12, 1058. https://doi.org/10.3390/vaccines12091058
Lapenta C, Santini SM, Antonacci C, Donati S, Cecchetti S, Frittelli P, Catalano P, Urbani F, Macchia I, Spada M, et al. Anti-Tumor Immunity to Patient-Derived Breast Cancer Cells by Vaccination with Interferon-Alpha-Conditioned Dendritic Cells (IFN-DC). Vaccines. 2024; 12(9):1058. https://doi.org/10.3390/vaccines12091058
Chicago/Turabian StyleLapenta, Caterina, Stefano Maria Santini, Celeste Antonacci, Simona Donati, Serena Cecchetti, Patrizia Frittelli, Piera Catalano, Francesca Urbani, Iole Macchia, Massimo Spada, and et al. 2024. "Anti-Tumor Immunity to Patient-Derived Breast Cancer Cells by Vaccination with Interferon-Alpha-Conditioned Dendritic Cells (IFN-DC)" Vaccines 12, no. 9: 1058. https://doi.org/10.3390/vaccines12091058