- Research article
- Open Access
Mature dendritic cells correlate with favorable immune infiltrate and improved prognosis in ovarian carcinoma patients
- Iva Truxova†1, 2,
- Lenka Kasikova†1, 2,
- Michal Hensler2,
- Petr Skapa3,
- Jan Laco4,
- Ladislav Pecen2,
- Lucie Belicova2,
- Ivan Praznovec5,
- Michael J. Halaska6,
- Tomas Brtnicky7,
- Eva Salkova3,
- Lukas Rob6,
- Roman Kodet3,
- Jeremy Goc8, 9, 10,
- Catherine Sautes-Fridman8, 9, 10,
- Wolf Herman Fridman8, 9, 10,
- Ales Ryska4,
- Lorenzo Galluzzi10, 11, 12,
- Radek Spisek1, 2 and
- Jitka Fucikova1, 2Email author
© The Author(s). 2018
- Received: 26 October 2018
- Accepted: 8 November 2018
- Published: 4 December 2018
A high density of tumor-infiltrating CD8+ T cells and CD20+ B cells correlates with prolonged survival in patients with a wide variety of human cancers, including high-grade serous ovarian carcinoma (HGSC). However, the potential impact of mature dendritic cells (DCs) in shaping the immune contexture of HGSC, their role in the establishment of T cell-dependent antitumor immunity, and their potential prognostic value for HGSC patients remain unclear. We harnessed immunohistochemical tests and biomolecular analyses to demonstrate that a high density of tumor-infiltrating DC-LAMP+ DCs is robustly associated with an immune contexture characterized by TH1 polarization and cytotoxic activity. We showed that both mature DCs and CD20+ B cells play a critical role in the generation of a clinically-favorable cytotoxic immune response in HGSC microenvironment. In line with this notion, robust tumor infiltration by both DC-LAMP+ DCs and CD20+ B cells was associated with most favorable overall survival in two independent cohorts of chemotherapy-naïve HGSC patients. Our findings suggest that the presence of mature, DC-LAMP+ DCs in the tumor microenvironment may represent a novel, powerful prognostic biomarker for HGSC patients that reflects the activation of clinically-relevant anticancer immunity.
- Dendritic cells
- CD8+ cytotoxic T lymphocytes
- Natural killer cells
- Tertiary lymphoid structures
Tumors emerge and evolve in the context of a complex metabolic, trophic and immunological crosstalk with cells of different types, including (but not limited to) epithelial, endothelial, stromal and immune cells [1, 2]. Thus, the microenvironment of solid malignancies exhibit a considerable degree of heterogeneity, not only across different types of disease, but also across the same tumor type in different patients or even different malignant lesions in the same individual . Not surprisingly, both non-immunological and immunological components of the tumor microenvironment (TME) have been attributed robust prognostic and/or predictive value in multiple cohorts of patients with cancer [4–8]. In particular, high levels of tumor-infiltrating CD8+ T lymphocytes (CTLs), which are key mediators of anticancer immunity, are strongly associated with prolonged survival in patients affected by various solid tumors including high-grade serous ovarian carcinoma (HGSC) [9–12]. Intriguingly, the majority of HGSCs containing high frequencies of CD8+ CTLs are also robustly infiltrated by CD20+ B cells , and patients whose tumors exhibit such an abundant co-infiltration have higher survival rates than patients with tumors that only contain high amounts of CD8+ CTLs [14, 15]. That said, the cellular mechanisms that govern the recruitment of CD8+ CTLs and CD20+ B cells to the microenvironment of HGSCs and their activation remain unclear.
It has previously been shown that CD8+ and CD20+ cells often co-localize in lymphoid aggregates of different sizes and morphologies in the HGSC microenvironment . These aggregates, which have previously been identified as tertiary lymphoid structures (TLSs), are known for their ability to initiate tumor-targeting immunity and for their positive prognostic value in patients with various tumor types [16–19]. TLSs harbor indeed prominent B-cell follicles adjacent to discrete zones containing CD4+ and CD8+ T cells, dendritic cells (DCs) and high endothelial venules [18, 20]. Since mature DCs selectively home to TLS, they constitute a reliable and specific marker of these structures [21, 22]. Nevertheless, the impact of mature DCs on the composition and functional orientation of the tumor infiltrate, their ability to drive T cell-dependent anticancer immunity, and their potential prognostic and predictive value in the setting of HGSC remain to be deciphered.
Here, we investigated the clinical impact of tumor infiltration by mature DCs in three independent cohorts of 81, 66 and 20 patients with resectable HGSC who did not received neoadjuvant chemotherapy. Our data suggest that while both mature DC-LAMP+ DCs and CD20+ B cells participate in the generation of anticancer immunity, only the former are critical for licensing a CTL-dependent tumor-targeting immune response that translates into clinical benefit for HGSC patients.
Main clinical and biological characteristics of 81 HGSC patients enrolled in the study (University Hospital Hradec Kralove)
Overall cohort (n = 81)
Mean age (y) ± SEM
61 ± 10
Stage III and IV
Vital status of patients
Tumor specimens from study groups 1 and 2 were fixed in neutral buffered 10% formalin solution and embedded in paraffin as per standard procedures. Immunostaining with antibodies specific for lysosomal associated membrane protein 3 (LAMP3; best known as DC-LAMP), CD8, CD20 and natural cytotoxicity triggering receptor 1 (NCR1; best known as NKp46) (Additional file 1: Table S2) was performed according to conventional protocols. Briefly, tissue sections were deparaffinized, followed by antigen retrieval with Target Retrieval Solution (Leica) in EDTA pH 8 in preheated water bath (98 °C, 30 min). The sections were allowed to cool down to RT for 30 min, and endogenous peroxidase was blocked with 3% H2O2 for 15 min. Thereafter, sections were treated with protein block (DAKO) for 15 min and incubated with primary antibodies, followed by the revelation of enzymatic activity. Images were acquired using a Leica Aperio AT2 scanner (Leica).
DC-LAMP+ cells were differentially quantified in the tumor stroma and tumor nests of the whole section with Calopix (Tribvn). The total number of CD8, NKp46 and CD20 density was analyzed on the entire tumor section of all 81 HGSC patients using Calopix software without further division for tumor stroma and tumor nest based on previous published protocols [14, 22, 25]. The NKp46 staining was performed based on previously optimized and published protocols [22, 25] and appropriate isotype controls were used throughout the study. The antibody against NKp46/NCR1 (R&D), clone 195,314 is suitable for immunohistochemistry analysis as indicated by manufacturer. Data are reported as absolute number of positive cells/mm2 (for DC-LAMP+, CD8+ NKp46+ cells) or cell surface/total tumor section surface (for CD20+ cells), as previously described [14, 21]. TLS were enumerated in whole sections using upon assessment of co-localizing DC-LAMP+ and CD20+ B cells, as previously described [14, 21]. Immunostaining and quantifications were reviewed by at least three independent observers (IT, LK, JF, PS, JL) and an expert pathologist (JL, PS).
Total live mononuclear cells were isolated from fresh tumor specimens, as previously described . Mononuclear cells were stained with several panels of fluorescent primary antibodies (Additional file 1: Table S3) or appropriate isotype controls for 20 min at 4 °C in the dark, following by washing and acquisition on a Fortessa flow cytometer (BD Bioscience). Flow cytometry data were analyzed with the FlowJo software (TreeStar). Gating strategies are depicted in Additional file 1: Figure S3A and 3C.
Degranulation and IFN-γ production after in vitro stimulation
Mononuclear cells isolated from fresh tumor specimens were stimulated with 50 ng/mL phorbol 12-myristate 13-acetate (PMA) + 1 μg/ml ionomycin in the presence of anti-CD107a FITC monoclonal antibody (BioLegend) for 1 h followed by 3 h incubation with brefeldin A (BioLegend). Unstimulated cells were used as control. Cells were then washed in PBS, stained with anti-CD45 PerCP (EXBIO), anti-CD3 Alexa Fluor 700 (EXBIO) or APC-eFluor780 (eBioscience), anti-CD4 ECD (Beckman Coulter), anti-CD8 HV500 (BD Biosciences) and anti-CD56 Alexa Fluor 700 (BioLegend) monoclonal antibodies, fixed in fixation/permeabilization buffer (eBioscience), permeabilized with permeabilization buffer (eBioscience) and stained with anti-IFN-γ PE-Cy7 (eBioscience), anti-granzyme B Brilliant Violet 421 (BD Biosciences) and anti-perforin APC (BioLegend) monoclonal antibodies. The percentage of CD3+CD8+ T cells and CD3−CD56+ NK cells producing IFN-γ and degranulating upon PMA/ionomycin stimulation were determined by flow cytometry. The data were analyzed with the FlowJo software package (Tree Star, Inc.).
NGS data analysis
Hierarchical clustering analysis was conducted for differentially expressed genes (DEGs) using the PHEATMAP package in R, based on The Euclidean distance and complete clustering method. GO, KEGG and REACTOME analyses were performed using ClueGo . The MCP-counter R package was used to estimate the abundance of tissue-infiltrating immune cell populations .
Survival analysis was performed using the Survival R package, using both log-rank tests and Cox proportional hazard regressions. For log-rank tests, the prognostic value of continuous variables was assessed using median-based cutoffs. For Cox proportional hazard regressions, immune densities were log-transformed. Variables that were not significantly associated with prognosis in univariate Cox regression (Wald test p > 0.05), as well as variables that were intrinsically correlated, were not included in multivariate Cox regressions. Fisher’s exact tests, Student’s t tests, and the Wilcoxon and Mann-Whitney tests were used to assess statistical significance, p values are reported (considered not significant when > 0.05).
Prognostic impact of mature DC infiltration in HGSC
Univariate Cox proportional hazard analysis
HR (95% Cl)
Multivariate Cox proportional hazard analysis
HR (95% Cl)
To evaluate the density of mature DCs within TLSs as well as the prognostic impact of the latter, we quantified TLSs by examining the co-localization of DC-LAMP+ DCs with CD20+ B cells. In line with previous findings , TLSs were only found in 10% of specimens from both cohorts of HGSC patients included in this study (data not shown). Next, we stratified patients from both cohorts based on the presence of TLSs within their TME and investigated whether TLSNeg and TLSPos patients differed in terms of OS. The presence of TLS did not influence OS in these retrospective cohorts of HGSC patients (Additional file 1: Figure S2, Table 2).
Mature DCs correlate with signs of a TH1-polarized effector immune response
Mature DCs are associated with HGSC infiltration by IFN-γ-producing CD8+ T cells
Mature DCs are associated with HGSC infiltration by cytotoxic NK cells
Both the innate and adaptive arm of the immune system contribute to cancer immunosurveillance . Thus, driven by the positive correlation between the density of mature DCs in the HGSC TME and the abundance of NK cell-related transcripts, we next evaluated the association between DC-LAMP+ DCs and NK cells by IHC (based on the specific NK cell marker NKp46) . NK cells were mainly localized to tumor invasive margin and stroma, were rarely in contact with malignant cells, and were generally found outside of TLSs (Fig. 3f). We observed a higher density of NK cells in the tumor stroma (but not in tumor nests) in DC-LAMPHi versus DC-LAMPLo samples (Fig. 3g), corroborating RNA-Seq data (Fig. 2c). To obtain insights into the functional capacity of NK cells infiltrating the TME, we used flow cytometry on freshly resected samples from a prospective cohort of 20 patients with HGSC (Additional file 1: Table S5), which were also analyzed for DC-LAMP+ cell density by IHC (Additional file 1: Figure S3C). We next compared the expression of 15 NK cell markers amongst CD3−CD56+ NK cells isolated from freshly resected DC-LAMPHi or DC-LAMPLo HGSCs. Although NK cell receptors were not differentially expressed in these two groups of samples (data not shown), non-specific stimulation was much more effective at inducing the acquisition of effector functions amongst NK cells from DC-LAMPHi patients (versus their DC-LAMPLo counterparts), as assessed by the percentage of NK cells expressing IFN-γ, IFN-γ/GZMB and IFN-γ/PRF1 (p = 0.046, p = 0.036 and p = 0.042, respectively) (Fig. 3h). These results suggest that intratumoral NK cells from DC-LAMPLo patients display an impaired capacity to acquire effector functions, even though their surface phenotype is unaltered.
Although NK cells have been associated with improved disease outcome in patients with some solid tumors , their prognostic impact on HGSC is unknown. We therefore stratified HGSC patients based on median NKp46+ cell density in the TME, finding no significant differences in OS between these two groups (Additional file 1: Figure S3D, Table 2). Importantly, when we stratified patients into four groups based on both DC-LAMP+ cell density and NKp46+ NK cell density, we observed that DC-LAMPHi/NKp46Hi patients had superior disease outcome (median OS > 120 mo.) as compared to DC-LAMPLo/NKp46Lo patients (median OS 26.5 mo.; p = 0.0005) (Fig. 3i).
CD20+ B cells in the HGSC TME correlate with mature DCs and long-term survival
Confirming prior observations , robust tumor infiltration by CD20+ B cells had a positive impact on the survival of patients with HGSC (p = 0.018) (Fig. 4f, Table 2). Importantly, high levels of both CD8+ CTLs and CD20+ B cells were associated with most favorable clinical outcome amongst the patients involved in this study (p = 0.049) (Fig. 4g). Indeed, median survival for CD8Hi/CD20Hi patients was > 120 mo., where it was only 47 mo. for CD8Lo/CD20Lo patients (p = 0.0004). These findings are in accordance with the results from survival analysis showing that DC-LAMPHi patients have the best OS irrespective of CD20+ B cell density (Fig. 4h). Altogether, our data suggest that while both mature DC-LAMP+ DCs and CD20+ B cells shape the immune contexture of HGSCs, only the former are critical for enabling a clinically relevant anticancer response driven by CD8+ CTLs.
Finally, we evaluated the combined prognostic value of DC-LAMP+, CD8+ and CD20+ cell density by stratifying our cohort in three groups of patients: DC-LAMPHi/CD8Hi/CD20Hi patients, DC-LAMPLo/CD8Lo/CD20Lo patients, and patients in which either of the three parameters was discordant with the remaining two (which we named DC-LAMP/CD8/CD20Mix). DC-LAMPHi/CD8Hi/CD20Hi patients had superior RFS (not shown) and OS (median > 120 mo.) compared with their DC-LAMPLo/CD8Lo/CD20Lo counterparts (median OS: 47 mo.) as well as DC-LAMP/CD8/CD20Mix patients (median OS 40 mo.) (Fig. 4i). Taken together, these findings indicate that the concomitant assessment of DC-LAMP+ DCs, CD20+ B cells and CD8+ CTLs in the TME of patients with HGSC conveys robust prognostic information.
The composition of the immune infiltrate in human solid tumors, its localization and functional orientation are major predictors of patient survival, as previously documented [5, 32]. In particular, high densities of intratumoral CD8+ CTLs and CD20+ B cells have been associated with improved clinical outcome in patients affected by a variety of tumors, including HGSC [13, 21]. Elevated intratumoral levels of DC-LAMP+ DCs also constitute a robust positive prognostic value in multiple oncological settings, including non-small-cell lung carcinoma (NSCLC) [14, 21, 33], melanoma , renal cell carcinoma (RCC) , breast cancer  and colorectal carcinoma (CRC) . Nevertheless, the impact of DC-LAMP+ cells on the composition and functional orientation of the immune contexture of HGSC and its prognostic role remained to be elucidated. Here, we assessed the prognostic value of DC-LAMP+ cell densities in two independent retrospective cohorts of patients with HGSC who did not receive neoadjuvant chemotherapy (n = 81 and n = 66).
We observed a major inter-individual variability in DC-LAMP+ cell densities. The great majority of mature DCs were localized in the tumor stroma and associated with TLSs (rather than being in direct contact with malignant cell nests), as previously observed in samples from NSCLC, RCC and CRC [14, 21, 22, 29]. In NSCLCs, mature DCs provide a specific marker for TLSs and constitute a favorable prognostic biomarker for survival [21, 33]. TLSs were identified only in 19% of our HGSC samples, which is in line with previous findings, and their abundance did not correlate with OS . We therefore decided to evaluate the prognostic impact of DC-LAMP+ DCs in the entire tumor stroma and tumor nest. High densities of mature DCs in the TME were strongly associated with improved RFS and, most importantly, superior OS in both independent retrospective cohorts.
By combining IHC and biomolecular analyses, we demonstrated that a high density of tumor-infiltrating mature DCs is associated with a TH1-polarized immune contexture that acquired effector functions. These results recapitulate previous findings in the setting of NSCLC [21, 33] and CRC [22, 36]. The presence of tumor-infiltrating CD8+ CTLs is strongly associated with improved clinical outcome amongst patients with HGSC [9, 12, 13]. Accordingly, we found a strong correlation between CD8+ CTL density and improved OS in our cohorts of HGSC patients. In both prospective and retrospective studies, we showed that CD8+ T cells co-localize preferentially with mature DCs in the HGSC TME, and that the density of CD8+ T cells is profoundly diminished in DC-LAMPLo tumors. DC-LAMPHi patients with a concomitantly elevated density of CD8+ CTLs in their tumors had a significant clinical benefit as compared to patients with low intratumoral levels of both mature DCs and CD8+ CTLs. Moreover, DC-LAMPLo/CD8Hi patients had significantly worse disease outcome than their DC-LAMPHi/CD8Hi counterparts. Thus, DC-LAMP stands out as a robust biomarker allowing for the identification of CD8Hi HGSC patients with higher risk of death.
In contrast to the well-established antitumor activity of CD8+ CTLs, there is little evidence in support of a similar function from NK cells (in the setting of HGSC) . NKp46+ NK cells were mainly localized at invasive tumor margins and within the stroma of HGSC samples, which is in line with previous finding in the NSCLC, CRC and RCC setting [22, 25]. Importantly, increased intratumoral levels of NK cells have been associated with good prognosis in patients with RCC, although a similar prognostic value could not be documented in NSCLC and CRC [22, 25]. Along similar lines, the density of NK cells did not influence clinical outcome in our cohorts of HGSC patients. Although the cell surface properties of NK cells did not differ between DC-LAMPHi and DC-LAMPLo samples, we observed significantly a higher frequency of IFN-γ+/PRF1+ and IFN-γ+/GZMB+ NK cells after non-specific stimulation in the former. Finally, in line with previous observations on CRC, DC-LAMPHi patients with concomitantly elevated amounts of intratumoral NK cells had a significant clinical benefit compared with DC-LAMPLo/NKp46Lo individuals . Taken together, our data demonstrate that robust tumor infiltration by mature DCs generates an immune contexture characterized by TH1 polarization and cytotoxic functions.
Importantly, the presence of CD20+ B cells correlates with improved OS in our cohorts of chemotherapy-naive patients with HGSC, which is line with previous observations from other oncological settings [13, 14, 38–41]. Notably, HGSCs containing elevated amounts of both CD8+ CTLs and CD20+ B cells are associated with superior survival than HGSCs containing high levels of either CD8+ CTLs or CD20+ B cells . These findings suggest not only the existence of cooperative interactions between CD8+ CTLs and CD20+ B cells in the TME of HGSCs, but also the critical role of B cells in regulation of the immune infiltrate, as previously reported in a variety of other cancers [42, 43]. CD8+ CTLs and CD20+ B cells often co-localize in lymphoid aggregates of various sizes and morphology in HGSC samples, as previously described in detail . In all such aggregates, especially in TLSs, B cells form follicles adjacent to discrete zones containing not only CD4+ and CD8+ T cells, but also high densities of DCs . Accordingly, we identified a robust correlation between the presence of DC-LAMP+ DCs and CD20+ B cells in the TME of HGSC lesions.
In conclusion, by combining IHC and biomolecular analyses, we comprehensively documented for the first time the influence of both mature DCs and CD20+ B cells on the establishment of the immune contexture of HGSC. That said, DCs stand out as the critical attribute for the initiation of an immune response to HGSC which exhibits TH1 polarization, is armed with immune effectors, and mediates clinical benefits. These findings are in line with previous studies documenting the critical role of mature DCs in the activation of antitumor immunity [44, 45]. Accordingly, we identified tumor infiltration by DC-LAMP+ DCs as a robust, positive prognostic biomarker for HGSC patients, as confirmed by both univariate and multivariate analyses.
This study was supported by the program PROGRES Q40/11 and PROGRES 28 (Oncology), by the project BBMRI-CZ LM2015089 and by the European Regional Development Fund-Project BBMRI-CZ.: Biobank network—a versatile platform for research on the etiopathogenesis of diseases, No: EF16 013/0001674. LG is supported by startup grant from the Department of Radiation Oncology at Weill Cornell Medicine (New York, US) and by donations from Phosplatin Therapeutics (New York, US), Sotio a.s. (Prague, Czech Republic) and the Luke Heller TECPR2 Foundation (Boston, US).
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Concept and design: PS, JL, AR, RS, JF; development of the methodology: IT, LK, MH, JF; acquisition of the data: IT, LK, LB, MH, ES, JF; analysis and interpretation of the data: IT, LK, MH, LP, IP, MH, TB, LR, RK, JG, JF; preparation, review, and/or revision of the manuscript and figures: IT, LK, MH, PS, JL, CSF, WHF, AR, LG, RS, JF; study supervision: RS, JF. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The study was approved by the ethics committees at the University Hospital Motol and University Hospital Hradec Kralove in accordance with Czech law.
Consent for publication
LG provides remunerated consulting to OmniSEQ (Buffalo, NY, USA), Astra Zeneca (Gaithersburg, MD, USA), VL47 (New York, NY, USA) and the Luke Heller TECPR2 Foundation (Boston, MA, USA). All other authors have no financial interests to disclose.
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