Abstract
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.
Highlights
It is accepted that tumors form, progress and respond to therapy in the context of an intimate, bidirectional interaction with the immune system [1, 2]
We demonstrate that CALR exposure on the surface of primary and metastatic high-grade serous carcinomas (HGSCs) cells is driven by a chemotherapy-independent endoplasmic reticulum (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
Our 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
Summary
It is accepted that tumors form, progress and respond to therapy in the context of an intimate, bidirectional interaction with the immune system [1, 2]. Kasikova et al Journal for ImmunoTherapy of Cancer (2019) 7:312 immunity by malignant cells undergoing immunogenic cell death [5, 6] In line with this notion, high expression levels of CALR and/or CALR exposure on the membrane of cancer cells have been linked with superior disease outcome in patients with colorectal carcinoma (CRC) [10], non-small cell lung carcinoma (NSCLC) [11, 12], acute myeloid leukemia (AML) [13], and ovarian cancer [11] generally in association with improved anticancer immunity. Adjuvanticity, 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. 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
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