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

Epithelial ovarian cancer (EOC) is among the top five causes of cancer-related death in women, largely reflecting early, prediagnosis dissemination of malignant cells to the peritoneum. Despite improvements in medical therapies, particularly with the implementation of novel drugs targeting homologous recombination deficiency, the survival rates of patients with EOC remain low. Unlike other neoplasms, EOC remains relatively insensitive to immune checkpoint inhibitors, which is correlated with a tumor microenvironment (TME) characterized by poor infiltration by immune cells and active immunosuppression dominated by immune components with tumor-promoting properties, especially tumor-associated macrophages (TAMs). In recent years, TAMs have attracted interest as potential therapeutic targets by seeking to reverse the immunosuppression in the TME and enhance the clinical efficacy of immunotherapy. Here, we review the key biological features of TAMs that affect tumor progression and their relevance as potential targets for treating EOC. We especially focus on the therapies that might modulate the recruitment, polarization, survival, and functional properties of TAMs in the TME of EOC that can be harnessed to develop superior combinatorial regimens with immunotherapy for the clinical care of patients with EOC.

• Keywords
• Immunomodulation, Immunotherapy, Macrophages, Tumor Biomarkers, Tumor Microenvironment,
• MeSH
• Carcinoma, Ovarian Epithelial therapy   pathology   MeSH
• Immunotherapy MeSH
• Carcinoma * pathology   MeSH
• Humans MeSH
• Tumor-Associated Macrophages pathology   MeSH
• Macrophages MeSH
• Tumor Microenvironment MeSH
• Ovarian Neoplasms * MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Dendritic cells (DCs) have received considerable attention as potential targets for the development of novel cancer immunotherapies. However, the clinical efficacy of DC-based vaccines remains suboptimal, largely reflecting local and systemic immunosuppression at baseline. An autologous DC-based vaccine (DCVAC) has recently been shown to improve progression-free survival and overall survival in randomized clinical trials enrolling patients with lung cancer (SLU01, NCT02470468) or ovarian carcinoma (SOV01, NCT02107937), but not metastatic castration-resistant prostate cancer (SP005, NCT02111577), despite a good safety profile across all cohorts. We performed biomolecular and cytofluorometric analyses on peripheral blood samples collected prior to immunotherapy from 1000 patients enrolled in these trials, with the objective of identifying immunological biomarkers that may improve the clinical management of DCVAC-treated patients. Gene signatures reflecting adaptive immunity and T cell activation were associated with favorable disease outcomes and responses to DCVAC in patients with prostate and lung cancer, but not ovarian carcinoma. By contrast, the clinical benefits of DCVAC were more pronounced among patients with ovarian carcinoma exhibiting reduced expression of T cell-associated genes, especially those linked to TH2-like signature and immunosuppressive regulatory T (TREG) cells. Clinical responses to DCVAC were accompanied by signs of antitumor immunity in the peripheral blood. Our findings suggest that circulating signatures of antitumor immunity may provide a useful tool for monitoring the potency of autologous DC-based immunotherapy.

• Keywords
• Cancer immunotherapy, anti-PD-1, circulating biomarkers, epithelial ovarian carcinoma, metastatic castrate-resistant prostate cancer, non-small cell lung carcinoma,
• MeSH
• Dendritic Cells metabolism   MeSH
• Carcinoma, Ovarian Epithelial drug therapy   MeSH
• Humans MeSH
• Lung Neoplasms * drug therapy   therapy   MeSH
• Ovarian Neoplasms * genetics   therapy   MeSH
• Cancer Vaccines * therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Cancer Vaccines * MeSH