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

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous disease that affects more than 800,000 patients worldwide each year. The variability of HNSCC is associated with differences in the carcinogenesis processes that are caused by two major etiological agents, namely, alcohol/tobacco, and human papillomavirus (HPV). Compared to non-virally induced carcinomas, the oropharyngeal tumors associated with HPV infection show markedly better clinical outcomes and are characterized by an immunologically "hot" landscape with high levels of tumor-infiltrating lymphocytes. However, the standard of care remains the same for both HPV-positive and HPV-negative HNSCC. Surprisingly, treatment de-escalation trials have not shown any clinical benefit in patients with HPV-positive tumors to date, most likely due to insufficient patient stratification. The in-depth analysis of the immune response, which places an emphasis on tumor-infiltrating immune cells, is a widely accepted prognostic tool that might significantly improve both the stratification of HNSCC patients in de-escalation trials and the development of novel immunotherapeutic approaches.

• Keywords
• antitumor immune response, head and neck squamous cell carcinoma, human papillomavirus (HPV), immune infiltrate, treatment de-escalation, tumor microenvironment,
• Publication type
• Journal Article MeSH
• Review MeSH

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.

• Keywords
• CD8+ cytotoxic T lymphocytes, DC-LAMP, Dendritic cells, Natural killer cells, Tertiary lymphoid structures,
• MeSH
• Biomarkers MeSH
• Dendritic Cells immunology   metabolism   pathology   MeSH
• Adult MeSH
• Immunophenotyping MeSH
• Immunohistochemistry MeSH
• Kaplan-Meier Estimate MeSH
• Carcinoma immunology   mortality   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Tumor Microenvironment immunology   MeSH
• Ovarian Neoplasms immunology   mortality   pathology   therapy   MeSH
• Prognosis MeSH
• Proportional Hazards Models MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Neoplasm Staging MeSH
• T-Lymphocyte Subsets immunology   metabolism   pathology   MeSH
• Lymphocytes, Tumor-Infiltrating immunology   metabolism   pathology   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
• Names of Substances
• Biomarkers MeSH

PURPOSE: We conducted an open-label, single-arm Phase I/II clinical trial in metastatic CRPC (mCRPC) patients eligible for docetaxel combined with treatment with autologous mature dendritic cells (DCs) pulsed with killed LNCaP prostate cancer cells (DCVAC/PCa). The primary and secondary endpoints were safety and immune responses, respectively. Overall survival (OS), followed as a part of the safety evaluation, was compared to the predicted OS according to the Halabi and MSKCC nomograms. EXPERIMENTAL DESIGN: Twenty-five patients with progressive mCRPC were enrolled. Treatment comprised of initial 7 days administration of metronomic cyclophosphamide 50 mg p.o. DCVAC/PCa treatment consisted of a median twelve doses of 1 × 107 dendritic cells per dose injected s.c. (Aldara creme was applied at the site of injection) during a one-year period. The initial 2 doses of DCVAC/PCa were administered at a 2-week interval, followed by the administration of docetaxel (75 mg/m2) and prednisone (5 mg twice daily) given every 3 weeks until toxicity or intolerance was observed. The DCVAC/PCa was then injected every 6 weeks up to the maximum number of doses manufactured from one leukapheresis. RESULTS: No serious DCVAC/PCa-related adverse events have been reported. The median OS was 19 months, whereas the predicted median OS was 11.8 months with the Halabi nomogram and 13 months with the MSKCC nomogram. Kaplan-Meier analyses showed that patients had a lower risk of death compared with both MSKCC (Hazard Ratio 0.26, 95% CI: 0.13-0.51) and Halabi (Hazard Ratio 0.33, 95% CI: 0.17-0.63) predictions. We observed a significant decrease in Tregs in the peripheral blood. The long-term administration of DCVAC/PCa led to the induction and maintenance of PSA specific T cells. We did not identify any immunological parameter that significantly correlated with better OS. CONCLUSIONS: In patients with mCRPC, the combined chemoimmunotherapy with DCVAC/PCa and docetaxel was safe and resulted in longer than expected survival. Concomitant chemotherapy did not preclude the induction of specific anti-tumor cytotoxic T cells.

• Keywords
• castration-resistant prostate cancer, dendritic cell, immunotherapy, overall survival, prostate cancer,
• MeSH
• Adenocarcinoma immunology   mortality   secondary   therapy   MeSH
• Chemotherapy, Adjuvant MeSH
• Antineoplastic Agents, Alkylating administration & dosage   MeSH
• Time Factors MeSH
• Cyclophosphamide administration & dosage   MeSH
• Dendritic Cells immunology   transplantation   MeSH
• Docetaxel MeSH
• Immunotherapy adverse effects   methods   mortality   MeSH
• Kaplan-Meier Estimate MeSH
• Middle Aged MeSH
• Humans MeSH
• Administration, Metronomic MeSH
• Prostatic Neoplasms, Castration-Resistant drug therapy   immunology   mortality   pathology   MeSH
• Nomograms MeSH
• Prednisone administration & dosage   MeSH
• Proportional Hazards Models MeSH
• Antineoplastic Combined Chemotherapy Protocols administration & dosage   adverse effects   MeSH
• Risk Factors MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• T-Lymphocyte Subsets immunology   MeSH
• Taxoids administration & dosage   MeSH
• Lymphocytes, Tumor-Infiltrating immunology   MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase I MeSH
• Clinical Trial, Phase II MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antineoplastic Agents, Alkylating MeSH
• Cyclophosphamide MeSH
• Docetaxel MeSH
• Prednisone MeSH
• Taxoids MeSH

Human papillomavirus (HPV) infection is one of the most important etiologic causes of oropharyngeal head and neck squamous cell carcinoma (HNSCC). Patients with HPV-positive HNSCC were reported to have a better clinical outcome than patients with HPV-negative cancers. However, little is known about the possible causes of different clinical outcomes. In this study, we analyzed a detailed immune profile of tumor samples from HNSCC patients with respect to their HPV status. We analyzed the characteristics of immune cell infiltrates, including the frequency and distribution of antigen-presenting cells and naïve, regulatory and effector T cells and the cytokine and chemokine levels in tumor tissue. There was a profound difference in the extent and characteristics of intratumoral immune cell infiltrates in HNSCC patients based on their HPV status. In contrast to HPV-negative tumor tissues, HPV-positive tumor samples showed significantly higher numbers of infiltrating IFNγ+ CD8+ T lymphocytes, IL-17+ CD8+ T lymphocytes, myeloid dendritic cells and proinflammatory chemokines. Furthermore, HPV-positive tumors had significantly lower expression of Cox-2 mRNA and higher expression of PD1 mRNA compared to HPV-negative tumors. The presence of a high level of intratumoral immune cell infiltrates might play a crucial role in the significantly better response of HPV-positive patients to standard therapy and their favorable clinical outcome. Furthermore, characterization of the HNSCC immune profile might be a valuable prognostic tool in addition to HPV status and might help identify novel targets for therapeutic strategies, including cancer immunotherapy.

• Keywords
• CD8+ T lymphocytes, Cox-2, cyclooxygenase 2, HNSCC, HNSCC, head and neck squamous cell carcinoma, HPV, HPV, human papillomavirus, PD-1, PD-1, programmed cell death 1, PD-L1, programmed cell death-ligand 1, Tim-3, Tim-3, T cell immunoglobulin and mucin protein 3, Treg, regulatory T cell, mDC, myeloid dendritic cell, pDC, plasmacytoic dendritic cell,
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH