“…5 Several clinical and pathological indicators have been introduced for estimating patient prognosis 6,7 however, while such systems are valuable, they mostly rely on clinical parameters or cancer cell-related factors. 6 The recently emerging role of the cancer cell-immune cell interface in shaping tumorigenesis [2][3][4] and the appearance of anticancer immunotherapy 8,9 has increased the need to identify new integrated as well as broad sets of prognostic biomarkers based on the cancer cell-immune cell interface.…”
The emerging role of the cancer cell-immune cell interface in shaping tumorigenesis/anticancer immunotherapy has increased the need to identify prognostic biomarkers. Henceforth, our primary aim was to identify the immunogenic cell death (ICD)-derived metagene signatures in breast, lung and ovarian cancer that associate with improved patient survival. To this end, we analyzed the prognostic impact of differential gene-expression of 33 pre-clinically-validated ICD-parameters through a large-scale metaanalysis involving 3,983 patients ('discovery' dataset) across lung (1,432), breast (1,115) and ovarian (1,436) malignancies. The main results were also substantiated in 'validation' datasets consisting of 818 patients of same cancer-types (i.e. 285 breast/274 lung/259 ovarian). The ICD-associated parameters exhibited a highly-clustered and largely cancer type-specific prognostic impact. Interestingly, we delineated ICDderived consensus-metagene signatures that exhibited a positive prognostic impact that was either cancer type-independent or specific. Importantly, most of these ICD-derived consensus-metagenes (acted as attractor-metagenes and thereby) 'attracted' highly co-expressing sets of genes or convergentmetagenes. These convergent-metagenes also exhibited positive prognostic impact in respective cancer types. Remarkably, we found that the cancer type-independent consensus-metagene acted as an 'attractor' for cancer-specific convergent-metagenes. This reaffirms that the immunological prognostic landscape of cancer tends to segregate between cancer-independent and cancer-type specific gene signatures. Moreover, this prognostic landscape was largely dominated by the classical T cell activity/ infiltration/function-related biomarkers. Interestingly, each cancer type tended to associate with biomarkers representing a specific T cell activity or function rather than pan-T cell biomarkers. Thus, our analysis confirms that ICD can serve as a platform for discovery of novel prognostic metagenes.
“…5 Several clinical and pathological indicators have been introduced for estimating patient prognosis 6,7 however, while such systems are valuable, they mostly rely on clinical parameters or cancer cell-related factors. 6 The recently emerging role of the cancer cell-immune cell interface in shaping tumorigenesis [2][3][4] and the appearance of anticancer immunotherapy 8,9 has increased the need to identify new integrated as well as broad sets of prognostic biomarkers based on the cancer cell-immune cell interface.…”
The emerging role of the cancer cell-immune cell interface in shaping tumorigenesis/anticancer immunotherapy has increased the need to identify prognostic biomarkers. Henceforth, our primary aim was to identify the immunogenic cell death (ICD)-derived metagene signatures in breast, lung and ovarian cancer that associate with improved patient survival. To this end, we analyzed the prognostic impact of differential gene-expression of 33 pre-clinically-validated ICD-parameters through a large-scale metaanalysis involving 3,983 patients ('discovery' dataset) across lung (1,432), breast (1,115) and ovarian (1,436) malignancies. The main results were also substantiated in 'validation' datasets consisting of 818 patients of same cancer-types (i.e. 285 breast/274 lung/259 ovarian). The ICD-associated parameters exhibited a highly-clustered and largely cancer type-specific prognostic impact. Interestingly, we delineated ICDderived consensus-metagene signatures that exhibited a positive prognostic impact that was either cancer type-independent or specific. Importantly, most of these ICD-derived consensus-metagenes (acted as attractor-metagenes and thereby) 'attracted' highly co-expressing sets of genes or convergentmetagenes. These convergent-metagenes also exhibited positive prognostic impact in respective cancer types. Remarkably, we found that the cancer type-independent consensus-metagene acted as an 'attractor' for cancer-specific convergent-metagenes. This reaffirms that the immunological prognostic landscape of cancer tends to segregate between cancer-independent and cancer-type specific gene signatures. Moreover, this prognostic landscape was largely dominated by the classical T cell activity/ infiltration/function-related biomarkers. Interestingly, each cancer type tended to associate with biomarkers representing a specific T cell activity or function rather than pan-T cell biomarkers. Thus, our analysis confirms that ICD can serve as a platform for discovery of novel prognostic metagenes.
“…Most DC vaccines could increase the overall survival by a couple of months with a number of reports describing tumor regression in about 15% of patients. Nevertheless, in a high number of patients no effective immune response can be induced despite the induction of tumor-specific T cells upon vaccination [21,75,76]. In part this can be explained by the advanced disease in most patients that were included in DC vaccination studies.…”
Section: The Hurdles Of Tumor-induced Immune Suppressionmentioning
Over the years research in the field of cancer immunotherapy has flourished, bringing about crucial breakthroughs, but at the same time revealing new and important pathways of immune suppression that put a break on the success of cancer immunotherapy. This review focuses on how nano-and micromaterials can be used to induce antitumor immune responses and what their role in overcoming immune suppression could be. It is now beyond question that this requires elegantly designed particles that can reach their target cells, deliver antigenic cargo and most importantly immune stimulants in order to provoke and sustain antitumor immunity.3
“…However, despite strong evidence of its utility in animal models and numerous clinical studies, there is limited evidence of widespread clinical efficacy. [1][2][3][4] Nonetheless, recent studies suggest that DC vaccination may have a place in treating both hematological and other malignancies; particularly if applied after a reduction in tumor burden following surgical resection, chemotherapy, or hematopoietic-stem-cell transplantation, when tumor immunosuppression is at its lowest. [5][6][7] Recent trials in acute myeloid leukemia (AML) [8][9][10] and multiple myeloma 7 investigating monocyte derived dendritic cell (Mo-DC) vaccination, after induction chemotherapy and transplantation, have demonstrated objective clinical and immunological responses.…”
Section: Introductionmentioning
confidence: 99%
“…19,20 The minor CD141 C XCR1 C mDC subset generates excellent cytotoxic T lymphocyte (CTL) responses due to their strong capacity to cross present antigen 17,21 but their low frequency makes their purification unrealistic using current technologies. 2 Immune-selected pDC have also been explored in the context of vaccination, and have been shown to induce T-cell responses in patients with melanoma. 22 The practical difficulties in isolating sufficient BDC led to the predominant use of in vitro cultured "DC-like" Mo-DC in the vast majority of clinical studies.…”
Section: Introductionmentioning
confidence: 99%
“…31,32 This suggests that the efficacy seen in some studies may relate to an adjuvant or antigen-transfer effect to host DC present at the site of injection. Replacing Mo-DC manufactured in vitro with primary BDC has two potential advantages: (1) BDC are likely to be superior antigen-presenting cells (APC), due to their specialized native antigen-presenting capacity and their potential to migrate more effectively than their in vitro counterparts; 1 (2) it simplifies the preparation, avoiding expensive long-term culture and regulatory processes.…”
There are numerous transcriptional, proteomic and functional differences between monocyte-derived dendritic cells (Mo-DC) and primary blood dendritic cells (BDC). The CMRF-56 monoclonal antibody (mAb) recognizes a cell surface marker, which is upregulated on BDC following overnight culture. Given its unique ability to select a heterogeneous population of BDC, we engineered a human chimeric (h)CMRF-56 IgG4 mAb to isolate primary BDC for potential therapeutic vaccination. The ability to select multiple primary BDC subsets from patients and load them with in vitro transcribed (IVT) mRNA encoding tumor antigen might circumvent the issues limiting the efficacy of Mo-DC. After optimizing and validating the purification of hCMRF-56 C BDC, we showed that transfection of hCMRF-56 C BDC with mRNA resulted in efficient mRNA translation and antigen presentation by myeloid BDC subsets, while preserving superior DC functions compared to Mo-DC. Immune selected and transfected hCMRF-56 C BDC migrated very efficiently in vitro and as effectively as cytokine matured Mo-DC in vivo. Compared to Mo-DC, hCMRF-56 C BDC transfected with influenza matrix protein M1 displayed superior MHC peptide presentation and generated potent antigen specific CD8 C T-cell recall responses, while Wilms tumor 1 (WT1) transfected CMRF-56 C BDC generated effective primary autologous cytotoxic T-cell responses. The ability of the combined DC subsets within hCMRF-56 C BDC to present mRNA delivered tumor antigens merits phase I evaluation as a reproducible generic platform for the next generation of active DC immune therapies.
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