PURPOSE: Patients with high-grade serous ovarian carcinoma (HGSOC) are virtually insensitive to immune checkpoint inhibitors (ICI) employed as standalone therapeutics, at least in part reflecting microenvironmental immunosuppression. Thus, conventional chemotherapeutics and targeted anticancer agents that not only mediate cytotoxic effects but also promote the recruitment of immune effector cells to the HGSOC microenvironment stand out as promising combinatorial partners for ICIs in this oncological indication. EXPERIMENTAL DESIGN: We harnessed a variety of transcriptomic, spatial, and functional assays to characterize the differential impact of neoadjuvant paclitaxel-carboplatin on the immunological configuration of paired primary and metastatic HGSOC biopsies as compared to neoadjuvant chemotherapy (NACT)-naïve HGSOC samples from five independent patient cohorts. RESULTS: We found NACT-driven endoplasmic reticulum stress and calreticulin exposure in metastatic HGSOC lesions culminates with the establishment of a dense immune infiltrate including follicular T cells (TFH cells), a prerequisite for mature tertiary lymphoid structure (TLS) formation. In this context, TLS maturation was associated with an increased intratumoral density of ICI-sensitive TCF1+PD1+ CD8+ T cells over their ICI-insensitive TIM-3+PD1+ counterparts. Consistent with this notion, chemotherapy coupled with a PD1-targeting ICI provided a significant survival benefit over either therapeutic approach in syngeneic models of HGSOC bearing high (but not low) tumor mutational burden. CONCLUSIONS: Altogether, our findings suggest that NACT promotes TLS formation and maturation in HGSOC lesions, de facto preserving an intratumoral ICI-sensitive T-cell phenotype. These observations emphasize the role of rational design, especially relative to the administration schedule, for clinical trials testing chemotherapy plus ICIs in patients with HGSOC. See related commentary by Bravo Melgar and Laoui, p. 10.

• MeSH
• CD8-Positive T-Lymphocytes * immunology   drug effects   MeSH
• Tertiary Lymphoid Structures * immunology   pathology   MeSH
• Hepatocyte Nuclear Factor 1-alpha * genetics   metabolism   MeSH
• Immune Checkpoint Inhibitors * therapeutic use   pharmacology   MeSH
• Carboplatin administration & dosage   pharmacology   therapeutic use   MeSH
• Humans MeSH
• Tumor Microenvironment * immunology   drug effects   MeSH
• Ovarian Neoplasms * drug therapy   immunology   pathology   MeSH
• Neoadjuvant Therapy methods   MeSH
• Paclitaxel administration & dosage   therapeutic use   pharmacology   MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   pharmacology   MeSH
• Cystadenocarcinoma, Serous drug therapy   pathology   immunology   MeSH
• Endoplasmic Reticulum Stress drug effects   immunology   MeSH
• Lymphocytes, Tumor-Infiltrating immunology   drug effects   metabolism   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Hepatocyte Nuclear Factor 1-alpha * MeSH
• Immune Checkpoint Inhibitors * MeSH
• Carboplatin MeSH
• Paclitaxel MeSH

PURPOSE: To understand prognostic immune cell infiltration signatures in neuroendocrine neoplasms (NENs), particularly pheochromocytoma and paraganglioma (PCPG), we analyzed tumor transcriptomic data from The Cancer Genome Atlas (TCGA) and other published tumor transcriptomic data of NENs. METHODS: We used CIBERSORT to infer immune cell infiltrations from bulk tumor transcriptomic data from PCPGs, in comparison to gastroenteropancreatic neuroendocrine tumors (GEPNETs) and small cell lung carcinomas (SCLCs). PCPG immune signature was validated with NanoString immune panel in an independent cohort. Unsupervised clustering of the immune infiltration scores from CIBERSORT was used to find immune clusters. A prognostic immune score model for PCPGs and the other NENs were calculated as a linear combination of the estimated infiltration of activated CD8+/CD4+ T cells, activated NK cells, and M0 and M2 macrophages. RESULTS: In PCPGs, we found five dominant immune clusters, associated with M2 macrophages, monocytes, activated NK cells, M0 macrophages and regulatory T cells, and CD8+/CD4+ T cells respectively. Non-metastatic tumors were associated with activated NK cells and metastatic tumors were associated with M0 macrophages and regulatory T cells. In GEPNETs and SCLCs, M0 macrophages and regulatory T cells were associated with unfavorable outcomes and features, such as metastasis and high-grade tumors. The prognostic immune score model for PCPGs and the NENs could predict non-aggressive and non-metastatic diseases. In PCPGs, the immune score was also an independent predictor of metastasis-free survival in a multivariate Cox regression analysis. CONCLUSION: The transcriptomic immune signature in PCPG correlates with clinical features like metastasis and prognosis.

• Keywords
• Biomarkers, Immunologic signature, Metastasis, Paraganglioma, Pheochromocytoma,
• MeSH
• Pheochromocytoma * genetics   MeSH
• Humans MeSH
• Biomarkers, Tumor MeSH
• Adrenal Gland Neoplasms * genetics   MeSH
• Pancreatic Neoplasms MeSH
• Stomach Neoplasms MeSH
• Neuroendocrine Tumors * genetics   MeSH
• Paraganglioma * genetics   MeSH
• Prognosis MeSH
• Intestinal Neoplasms MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 4-carboxyphenylglyoxal MeSH Browser
• Biomarkers, Tumor MeSH

Epithelial ovarian carcinoma (EOC) is a relatively rare malignancy but is the fifth-leading cause of cancer-related death in women, largely reflecting early, prediagnosis dissemination of malignant disease to the peritoneum. At odds with other neoplasms, EOC is virtually insensitive to immune checkpoint inhibitors, correlating with a tumor microenvironment that exhibits poor infiltration by immune cells and active immunosuppression. Here, we comparatively summarize the humoral and cellular features of primary and metastatic EOC, comparatively analyze their impact on disease outcome, and propose measures to alter them in support of treatment sensitivity and superior patient survival.

• Keywords
• female, genital neoplasms, immunologic surveillance, immunotherapy, tumor biomarkers, tumor microenvironment,
• MeSH
• Carcinoma, Ovarian Epithelial immunology   MeSH
• Immunosuppression Therapy methods   MeSH
• Immunotherapy methods   MeSH
• Humans MeSH
• Tumor Microenvironment MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

BACKGROUND: The immunological microenvironment of primary high-grade serous carcinomas (HGSCs) has a major impact on disease outcome. Conversely, little is known on the microenvironment of metastatic HGSCs and its potential influence on patient survival. Here, we explore the clinical relevance of the immunological configuration of HGSC metastases. METHODS: RNA sequencing was employed on 24 paired primary tumor microenvironment (P-TME) and metastatic tumor microenvironment (M-TME) chemotherapy-naive HGSC samples. Immunohistochemistry was used to evaluate infiltration by CD8+ T cells, CD20+ B cells, DC-LAMP+ (lysosomal-associated membrane protein 3) dendritic cells (DCs), NKp46+ (natural killer) cells and CD68+CD163+ M2-like tumor-associated macrophages (TAMs), abundance of PD-1+ (programmed cell death 1), LAG-3+ (lymphocyte-activating gene 3) cells, and PD-L1 (programmed death ligand 1) expression in 80 samples. Flow cytometry was used for functional assessments on freshly resected HGSC samples. RESULTS: 1468 genes were differentially expressed in the P-TME versus M-TME of HGSCs, the latter displaying signatures of extracellular matrix remodeling and immune infiltration. M-TME infiltration by immune effector cells had little impact on patient survival. Accordingly, M-TME-infiltrating T cells were functionally impaired, but not upon checkpoint activation. Conversely, cytokine signaling in favor of M2-like TAMs activity appeared to underlie inhibited immunity in the M-TME and poor disease outcome. CONCLUSIONS: Immunosuppressive M2-like TAM infiltrating metastatic sites limit clinically relevant immune responses against HGSCs.

• Keywords
• macrophages, tumor biomarkers, tumor microenvironment,
• MeSH
• Immunosuppression Therapy methods   MeSH
• Middle Aged MeSH
• Humans MeSH
• Macrophages immunology   MeSH
• Neoplasm Metastasis MeSH
• Biomarkers, Tumor metabolism   MeSH
• Tumor Microenvironment MeSH
• Ovarian Neoplasms immunology   MeSH
• Retrospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Names of Substances
• Biomarkers, Tumor MeSH

BACKGROUND: 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. 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. METHOD: We 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. RESULTS: We 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. CONCLUSIONS: 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.

• Keywords
• B cells, CD20, Cancer immunotherapy, DC-LAMP, Dendritic cells, Immunogenic cell death,
• MeSH
• Adult MeSH
• Calreticulin immunology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Tumor Microenvironment genetics   immunology   MeSH
• Ovarian Neoplasms genetics   immunology   MeSH
• Prognosis MeSH
• RNA-Seq MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Endoplasmic Reticulum Stress MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Names of Substances
• CALR protein, human MeSH Browser
• Calreticulin MeSH

Dendritic cells (DCs) are key regulators of immune responses that operate at the interface between innate and adaptive immunity, and defects in DC functions contribute to the pathogenesis of a variety of disorders. For instance, cancer evolves in the context of limited DC activity, and some autoimmune diseases are initiated by DC-dependent antigen presentation. Thus, correcting aberrant DC functions stands out as a promising therapeutic paradigm for a variety of diseases, as demonstrated by an abundant preclinical and clinical literature accumulating over the past two decades. However, the therapeutic potential of DC-targeting approaches remains to be fully exploited in the clinic. Here, we discuss the unique features of DCs that underlie the high therapeutic potential of DC-targeting strategies and critically analyze the obstacles that have prevented the full realization of this promising paradigm.

• Keywords
• autoimmune disorders, cancer, dendritic cells, immunotherapy, vaccine preparation,
• MeSH
• Antigen-Presenting Cells immunology   metabolism   MeSH
• Autoimmunity MeSH
• Autoimmune Diseases etiology   metabolism   therapy   MeSH
• Cell Differentiation genetics   immunology   MeSH
• Dendritic Cells immunology   metabolism   MeSH
• Immunity * MeSH
• Immune Tolerance * MeSH
• Immunotherapy MeSH
• Humans MeSH
• Cell Communication MeSH
• Disease Susceptibility MeSH
• Neoplasms etiology   metabolism   pathology   therapy   MeSH
• Cell Plasticity genetics   immunology   MeSH
• Antigen Presentation immunology   MeSH
• Cancer Vaccines administration & dosage   immunology   MeSH
• T-Lymphocytes immunology   metabolism   MeSH
• Treatment Outcome MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Cancer Vaccines MeSH