In multiple oncological settings, expression of the coinhibitory ligand PD-L1 by malignant cells and tumor infiltration by immune cells expressing coinhibitory receptors such as PD-1, CTLA4, LAG-3, ...or TIM-3 conveys prognostic or predictive information. Conversely, the impact of these features of the tumor microenvironment on disease outcome among high-grade serous carcinoma (HGSC) patients remains controversial.
We harnessed a retrospective cohort of 80 chemotherapy-naïve HGSC patients to investigate PD-L1 expression and tumor infiltration by CD8
T cells, CD20
B cells, DC-LAMP
dendritic cells as well as by PD-1
, CTLA4
, LAG-3
, and TIM-3
cells in relation with prognosis and function orientation of the tumor microenvironment. IHC data were complemented with transcriptomic and functional studies on a second prospective cohort of freshly resected HGSC samples.
analysis of publicly available RNA expression data from 308 HGSC samples was used as a confirmatory approach.
High levels of PD-L1 and high densities of PD-1
cells in the microenvironment of HGSCs were strongly associated with an immune contexture characterized by a robust T
1 polarization and cytotoxic orientation that enabled superior clinical benefits. Moreover, PD-1
TIM-3
CD8
T cells presented all features of functional exhaustion and correlated with poor disease outcome. However, although PD-L1 levels and tumor infiltration by TIM-3
cells improved patient stratification based on the intratumoral abundance of CD8
T cells, the amount of PD-1
cells failed to do so.
Our data indicate that PD-L1 and TIM-3 constitute prognostically relevant biomarkers of active and suppressed immune responses against HGSC, respectively.
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 T
1 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.
BackgroundAdjuvanticity, which is the ability of neoplastic cells to deliver danger signals, is critical for the host immune system to mount spontaneous and therapy-driven anticancer immune ...responses. One of such signals, i.e., the exposure of calreticulin (CALR) on the membrane of malignant cells experiencing endoplasmic reticulum (ER) stress, is well known for its role in the activation of immune responses to dying cancer cells. However, the potential impact of CALR on the immune contexture of primary and metastatic high-grade serous carcinomas (HGSCs) and its prognostic value for patients with HGSC remains unclear.MethodWe harnessed a retrospective cohort of primary (no = 152) and metastatic (no = 74) tumor samples from HGSC patients to investigate the CALR expression in relation with prognosis and function orientation of the tumor microenvironment. IHC data were complemented with transcriptomic and functional studies on second prospective cohort of freshly resected HGSC samples. In silico analysis of publicly available RNA expression data from 302 HGSC samples was used as a confirmatory approach.ResultsWe demonstrate that CALR exposure on the surface of primary and metastatic HGSC cells is driven by a chemotherapy-independent ER stress response and culminates with the establishment of a local immune contexture characterized by TH1 polarization and cytotoxic activity that enables superior clinical benefits.ConclusionsOur data indicate that CALR levels in primary and metastatic HGSC samples have robust prognostic value linked to the activation of clinically-relevant innate and adaptive anticancer immune responses.
Abstract
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-naive 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.
Citation Format: Iva Truxova, Lenka Kasikova, Michal Hensler, Petr Skapa, Jan Laco, Ladislav Pecen, Lucie Belicova, Ivan Praznovec, Michael J. Halaska, Tomas Brtnicky, Eva Salkova, Lukas Rob, Roman Kodet, Jeremy Goc, Catherine Sautes-Fridman, Wolf Herman Fridman, Ales Ryska, Lorenzo Galluzzi, Radek Spisek, Jitka Fucikova. Mature dendritic cells correlate with favorable immune infiltrate and improved prognosis in ovarian carcinoma patients abstract. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B76.
Abstract
A high density of tumor-infiltrating CD8+ T lymphocytes (CTLs), key mediator of anticancer immunity, and CD20+ B cells correlates with positive prognostic value and prolonged survival in ...patients with a various solid tumors including high-grade serous ovarian carcinoma (HGSC). The majority of HGSCs containing high frequencies of CD8+ CTLs are also robustly infiltrated by CD20+ B cells, and patients whose tumors exhibit abundant coinfiltration have higher survival rates than patients with tumors that only contain high amounts of CD8+ CTLs. However, the cellular mechanism, 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. Three independent cohorts of patients with resectable HGSC who did not receive neoadjuvant chemotherapy were involved in the study. Lysosomal-associated membrane protein 3 (DC-LAMP) and its colocalization with CD20+B cells in samples was analyzed by immunohistochemistry (IHC) and cell quantification. Prognostic impact of DC-LAMP+ cells in patient cohort was stratified based on median density of DC-LAMP+ cells in the tumor stroma and nest, followed by retrospective RFS and OS analysis. Comparison of DC-LAMPHi and DC-LAMPLo patients and impact of mature DCs on the composition of the immune contexture characterized by TH1 polarization and cytotoxic activity was performed by biomolecular analyses (flow cytometry, NGS analysis). Patients with high density of DC-LAMP+ cells in the tumor stroma exhibited significantly longer RFS and OS than DC-LAMP- patients. Compared to DC-LAMPLo, DC-LAMPHi tumors exhibited an over-representation of gene sets specifically clustering to the following immunologic functions: T cells, CD8 cytotoxicity, TH1 polarization, T cell activation, NK cells, and plasma cells. Also, a significantly higher percentage of CD3+CD45+ and CD3+CD8+ T cells among live mononuclear cells and higher density of NK cells in the tumor stroma in DC-LAMPHi were observed. We found 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. Robust tumor infiltration by both DC-LAMP+ DCs and CD20+ B cells was associated with most favorable overall survival in independent cohorts of chemotherapy-naive 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.
Citation Format: Iva Truxova, Lenka Kasikova, Michal Hensler, Petr Skapa, Jan Laco, Ladislav Pecen, Lucie Belicova, Sarka Vosahlikova, Ivan Praznovec, Michael Halaska, Tomas Brtnicky, Eva Salkova, Lukas Rob, Roman Kodet, Jeremy Goc, Catherine Sautes-Fridman, Wolf Herve Fridman, Ales Ryska, Lorenzo Galluzzi, Radek Spisek, Jitka Fucikova. Mature dendritic cells correlate with favorable immune infiltrate and improved prognosis in ovarian carcinoma patients abstract. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A24.
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