• cancar immunotherapy
• gynaecologic oncology
• immune-checkpoint inhibitors
• immuno-cell therapy
• oncoimmunology

• Hormesis
• Immune response curve
• Mixed response curve
• Radio-chemotherapy response curve
• Synergy
• Tumour

• Humans
• Hormesis
• Neoplasms/therapy
• Immunotherapy/adverse effects
• Cytokines

• 12031010 National Natural Science Foundation of China
• 12171295 National Natural Science Foundation of China
• 12126350 National Natural Science Foundation of China
• 12101488 National Natural Science Foundation of China
• 2022KJXX-29 Project of Science and Technology Young Star in Shaanxi Province

• CAR-T therapy
• EGFR
• Icam1
• NF-κB
• radiation
• triple-negative breast cancer

• Humans
• Mice
• Animals
• Triple Negative Breast Neoplasms/genetics
• Triple Negative Breast Neoplasms/radiotherapy
• Receptors, Chimeric Antigen/genetics
• NF-kappa B/genetics
• Xenograft Model Antitumor Assays
• ErbB Receptors/genetics
• ErbB Receptors/metabolism
• T-Lymphocytes
• Cell Line, Tumor
• Intercellular Adhesion Molecule-1/genetics

• Dendritic Cells
• Female
• Humans
• Male
• Melanoma
• Peptides
• Retrospective Studies

• P 29919 Austrian Science Fund FWF

• Doxil®
• antitumor immunity
• chemotherapy
• doxorubicin (DXR)
• drug delivery system

The potential of dendritic cell (DC)-based immunotherapy to treat cancer is, nowadays, well documented. Still, the clinical success of immune checkpoint inhibitors has dampened the interest in anticancer DC vaccination. For highly life-threatening tumors that are regarded as nonimmunogenic, such as mesothelioma, however, T helper 1 immunity-biased DC-based immunotherapy could still represent an attractive strategy. In this study, we took advantage of photodynamic therapy (PDT) to induce immunogenic cell death to generate mesothelioma cell lysates for DC priming and evaluated such a vaccine to treat peritoneal mesothelioma. We found that the white light in vitro activation of the photosensitizer OR141 led to mesothelioma cell death, together with the release of bona fide danger signals that promote DC maturation. The administration of a PDT-based DC vaccine to mice bearing peritoneal mesothelioma led to highly significant survival when compared with sham or control animals treated with anti-CTLA4 antibodies. This was further supported by a strong CD8⁺ and CD4⁺ T cell response, characterized by an increased proliferation, cytotoxic activities and the expression of activation markers, including interferon gamma (IFNγ). Moreover, the PDT-based DC vaccine led to a significant increase in IFNγ⁺ T cells infiltered within mesothelioma, as determined by flow cytometry and immunohistochemistry. Finally, in vivo tracking of intraperitoneally administered DCs led us to document rapid chemotaxis towards tumor-occupied lymphatics (vs. lipopolysaccharide (LPS)-treated DC). DCs pulsed with PDT-killed mesothelioma cells also exhibited a significant increase in CCR7 receptors, together with an intrinsic capacity to migrate towards the lymph nodes. Altogether, these results indicate that PDT-based DC vaccination is particularly suited to induce a potent immune response against peritoneal mesothelioma.

• danger-associated molecular patterns (DAMPs), radiotherapy
• immunogenic cell death
• photodynamic therapy
• vaccination

• 34D20
• 34H20
• 37M25
• 92B05
• Competition model
• bifurcation analysis
• cancer
• dynamical system
• numerical simulation

• Cell Proliferation
• Computer Simulation
• Humans
• Models, Biological
• Neoplasms/drug therapy
• Neoplasms/pathology
• Numerical Analysis, Computer-Assisted

• chemotherapy
• immunotherapy
• multiplexed fluorescence imaging
• the second near-infrared window
• tumor therapy

• Animals
• Breast Neoplasms/drug therapy
• Breast Neoplasms/immunology
• Breast Neoplasms/pathology
• Breast Neoplasms/therapy
• Cell Line, Tumor
• Humans
• Immunotherapy/methods
• Infrared Rays
• Mice
• Optical Imaging

The platinum(II) complexes carboplatin (CBDCA), cisplatin (CDDP) and oxaliplatin (1-OHP) are used as anticancer drugs in a large number of tumour chemotherapy regimens. Many attempts have been made to combine Pt(II)-based chemotherapy with alternative treatment strategies. One such alternative anticancer approach is known as photodynamic therapy (PDT), where a non-toxic photosensitizer (PS) produces oxidative stress via the formation of reactive oxygen species (ROS) after local illumination of the affected tissue. A very promising PS is 5,10,15,20-tetra(m-hydroxyphenyl)chlorin (mTHPC, Temoporfin), which is approved for the treatment of head and neck cancer in Europe. In the present study, a combination of mTHPC-mediated PDT and either CBDCA, CDDP, or 1-OHP was applied to five human cancer cell lines from different tumour origins. Cytotoxicity was determined by the MTT assay and synergistic effects on cytotoxicity were evaluated by calculation of Combination Indices (CI). Synergy was identified in some of the combinations, for example, with 1-OHP in three of the tested cell lines but antagonism was also observed for a number of combinations in certain cell lines. In cases of synergy, elevated ROS levels were observed after combination but apoptosis induction was not necessarily increased compared to a treatment with a single compound. Cell cycle analysis revealed a formation of apoptotic subG1 populations and S phase as well as G2/M phase arrests after combination. In conclusion, pre-treatment with mTHPC-PDT has the potential to sensitize some types of tumour cells towards Pt(II) complexes, in particular 1-OHP but synergy is highly dependent on the type of cancer.

• Pt(II) complexes
• cancer therapy
• carboplatin
• cisplatin
• combination assay
• mTHPC
• oxaliplatin
• photodynamic therapy
• synergism

• click chemistry
• drug delivery
• immune checkpoint inhibitor
• immunochemotherapy
• immunogenic cell death (ICD)

• Animals
• Cell Line, Tumor
• Click Chemistry
• Immunotherapy
• Mice
• Mice, Inbred C57BL
• Neoplasms
• T-Lymphocytes

• Breast cancer
• GR1
• Immunohistochemistry
• MDSC
• S100A8/A9

• Cancer
• Immune system
• Immunotherapy
• Mathematical model
• Optimization
• Tumor

• Biomarkers
• Cetuximab
• Combination regimen
• Head and neck cancer
• Immunotherapy
• Metastatic
• Nivolumab
• Pembrolizumab
• Recurrent
• Targeted therapy

• cancer vaccines
• cell fusions
• cytotoxic T lymphocyte
• dendritic cell
• whole tumor cell

• Animals
• Antigens, Neoplasm/metabolism
• CD4-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/immunology
• Cancer Vaccines/immunology
• Cell Fusion
• Dendritic Cells/cytology
• Dendritic Cells/immunology
• Histocompatibility Antigens Class I/metabolism
• Histocompatibility Antigens Class II/metabolism
• Humans
• Lymphocyte Activation
• Tumor Cells, Cultured/cytology
• Tumor Cells, Cultured/immunology

• Cancer vaccine
• Cytotoxic T lymphocyte
• Dendritic cell
• Pancreatic cancer
• Whole tumor cell

• Adaptive Immunity
• Animals
• Antibodies/therapeutic use
• Antigens, Neoplasm/genetics
• Antigens, Neoplasm/immunology
• Antineoplastic Agents/therapeutic use
• Cancer Vaccines/adverse effects
• Cancer Vaccines/genetics
• Cancer Vaccines/immunology
• Cancer Vaccines/therapeutic use
• Carcinoma, Pancreatic Ductal/drug therapy
• Carcinoma, Pancreatic Ductal/genetics
• Carcinoma, Pancreatic Ductal/immunology
• Carcinoma, Pancreatic Ductal/pathology
• Cell Transplantation/adverse effects
• Cell Transplantation/methods
• Chemotherapy, Adjuvant
• Dendritic Cells/immunology
• Dendritic Cells/transplantation
• Genetic Therapy/adverse effects
• Genetic Therapy/methods
• Humans
• Lymphocytes, Tumor-Infiltrating/immunology
• Pancreatic Neoplasms/drug therapy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/immunology
• Pancreatic Neoplasms/pathology
• Treatment Outcome
• Tumor Escape
• Tumor Microenvironment

Human chorionic gonadotropin (hCG) has essential roles in pregnancy. Reports linking hCG in non-trophoblastic tumors with poor patient prognosis has spurred interest in patho-physiological roles the hormone might play.

The ability of hCG to prevent tumor cell death and sustain viability in the presence of chemotherapeutic drugs was assessed and potential synergies with TLR ligands explored. hCG-induced up-modulation of genes involved in chemoresistance was documented and targets validated by siRNA knock-down. Whether hCG could drive collaboration between tumor cells and macrophages in the production of IL-6 and consequent chemoresistance was assessed. The effects of concurrent anti-hCG immunization and chemotherapy on the growth of syngeneic murine tumors were evaluated.

hCG maintained basal levels of cytokine secretion by tumor cells exposed to chemotherapeutic drugs, and enhanced viability and proliferation; pre-treatment with hCG also decreased apoptosis, as assessed by Annexin-V binding and the cleavage of caspase 3. While co-incubation with hCG along with several TLR ligands mediated heightened chemo-resistance, TLR-2/6 and TLR-9 ligands increased the phosphorylation of JNK, and TLR-2 and TLR-8 ligands the phosphorylation of ERK in presence of hCG and curcumin, providing evidence of tri-molecular synergy. The hormone increased the transcription and/or expression of molecular intermediates (SURVIVIN, HIF-1α, PARP-1, Bcl-2, c-FLIP, KLK-10, XIAP, c-IAP-1) associated with chemo-resistance and increased levels of stress modulators (PON2, HO-1, HSP27 and NRF-2). siRNAs to SURVIVIN, NRF-2, HO-1 and HIF-1α attenuated hCG-mediated chemo-resistance. hCG-conditioned tumor cell supernatants induced heightened secretion of IL-6 and TNF-α from peripheral blood adherent cells and secreted IL-6 imparted chemo-resistance to naïve tumor cells. Co-administration of curcumin along with an anti-hCG vaccine (hCGβ conjugated to Tetanus Toxoid (TT)) to mice carrying syngeneic tumors resulted in significantly enhanced benefits on animal survival; synergy was demonstrated between anti-hCG antibodies and curcumin in the reduction of tumor cell viability.

The data suggest that hCG, via direct as well as collaborative effects with TLR ligands and accessory cell-secreted cytokines, mediates chemo-resistance in gonadotropin-sensitive tumors and outlines the potential benefits of combination therapy.

The online version of this article (doi:10.1186/s12885-015-1938-x) contains supplementary material, which is available to authorized users.

Interferon (IFN)-γ-mediated immune response plays an important role in tumor immunosurveillance. However, the regulation of IFN-γ-mediated tumorigenesis and immune response remains elusive. USP18, an interferon stimulating response element, regulates IFN-α-mediated signaling in anti-viral immune response, but its role in IFN-γ-mediated tumorigenesis and anti-tumor immune response is unknown.

In this study, USP18 in tumorigenesis and anti-tumor immune response was comprehensively appraised in vivo by overexpression or downregulation its expression in murine B16 melanoma tumor model in immunocompetent and immunodeficient mice.

Ectopic expression or downregulation of USP18 in B16 melanoma tumor cells inhibited or promoted tumorigenesis, respectively, in immunocompetent mice. USP18 expression in B16 melanoma tumor cells regulated IFN-γ-mediated immunoediting, including upregulating MHC class-I expression, reducing tumor cell-mediated inhibition of T cell proliferation and activation, and suppressing PD-1 expression in CD4⁺ and CD8⁺ T cells in tumor-bearing mice. USP18 expression in B16 melanoma tumor cells also enhanced CTL activity during adoptive immunotherapy by prolonging the persistence and enhancing the activity of adoptively transferred CTLs and by reducing CTL exhaustion in the tumor microenvironment. Mechanistic studies demonstrated that USP18 suppressed tumor cell-mediated immune inhibition by activating T cells, inhibiting T-cell exhaustion, and reducing dendritic cell tolerance, thus sensitizing tumor cells to immunosurveillance and immunotherapy.

These findings suggest that stimulating USP18 is a feasible approach to induce B16 melanoma specific immune response.

• Aged
• Cancer Vaccines/therapeutic use
• Cytokines/metabolism
• Dendritic Cells/cytology
• Female
• Humans
• Lung Neoplasms/immunology
• Lung Neoplasms/therapy
• Male
• Middle Aged
• Myeloid Cells/cytology
• Phenotype
• Small Cell Lung Carcinoma/immunology
• Small Cell Lung Carcinoma/therapy
• Tretinoin/metabolism
• Tumor Suppressor Protein p53/metabolism

• P30 CA076292 NCI NIH HHS
• P50 CA119997 NCI NIH HHS

• survivin
• tumor vaccine
• prime-boost
• immunoadjuvant
• chemotherapeutics

• Adenoviridae/genetics
• Adjuvants, Immunologic/therapeutic use
• Animals
• Antigens, Neoplasm/genetics
• Antigens, Neoplasm/immunology
• Antineoplastic Agents/therapeutic use
• Cancer Vaccines/genetics
• Cancer Vaccines/immunology
• Cancer Vaccines/therapeutic use
• Carboplatin/therapeutic use
• Cell Line, Tumor
• Combined Modality Therapy
• Female
• Humans
• Inhibitor of Apoptosis Proteins/genetics
• Inhibitor of Apoptosis Proteins/immunology
• Interleukin-2/therapeutic use
• Melanoma, Experimental/drug therapy
• Melanoma, Experimental/immunology
• Melanoma, Experimental/therapy
• Mice
• Mice, Inbred C57BL
• Mutation
• Skin Neoplasms/drug therapy
• Skin Neoplasms/immunology
• Skin Neoplasms/therapy
• Survivin
• Treatment Outcome
• Vaccines, DNA/genetics
• Vaccines, DNA/immunology
• Vaccines, DNA/therapeutic use

Pancreatic cancer is a highly aggressive and notoriously difficult to treat. As the vast majority of patients are diagnosed at advanced stage of the disease, only a small population is curative by surgical resection. Although gemcitabine-based chemotherapy is typically offered as standard of care, most patients do not survive longer than 6 months. Thus, new therapeutic approaches are needed. Pancreatic cancer cells that develop gemcitabine resistance would still be suitable targets for immunotherapy. Therefore, one promising treatment approach may be immunotherapy that is designed to target pancreatic-cancer-associated antigens. In this paper, we detail recent work in immunotherapy and the advances in concept of combination therapy of immunotherapy and chemotherapy. We offer our perspective on how to increase the clinical efficacy of immunotherapies for pancreatic cancer.

• immunotherapy
• melanoma
• interleukin-2
• intralesional injection
• in situ vaccination
• intransit metastases

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Female
• Follow-Up Studies
• Humans
• Interleukin-2/administration & dosage
• Interleukin-2/therapeutic use
• Kaplan-Meier Estimate
• Male
• Melanoma/drug therapy
• Melanoma/mortality
• Melanoma/pathology
• Middle Aged
• Neoplasm Metastasis/drug therapy
• Neoplasm Metastasis/pathology
• Neoplasm Staging
• Skin Neoplasms/drug therapy
• Skin Neoplasms/mortality
• Skin Neoplasms/pathology
• Treatment Outcome
• Young Adult

The dose-delivery schedule of conventional chemotherapy, which determines its efficacy and toxicity, is based on the maximum tolerated dose. This strategy has lead to cure and disease control in a significant number of patients but is associated with significant short-term and long-term toxicity. Recent data demonstrate that moderately low-dose chemotherapy may be efficiently combined with immunotherapy, particularly with dendritic cell (DC) vaccines, to improve the overall therapeutic efficacy. However, the direct effects of low and ultra-low concentrations on DCs are still unknown. Here we characterized the effects of low noncytotoxic concentrations of different classes of chemotherapeutic agents on human DCs in vitro. DCs treated with antimicrotubule agents vincristine, vinblastine, and paclitaxel or with antimetabolites 5-aza-2-deoxycytidine and methotrexate, showed increased expression of CD83 and CD40 molecules. Expression of CD80 on DCs was also stimulated by vinblastine, paclitaxel, azacytidine, methotrexate, and mitomycin C used in low nontoxic concentrations. Furthermore, 5-aza-2-deoxycytidine, methotrexate, and mitomycin C increased the ability of human DCs to stimulate proliferation of allogeneic T lymphocytes. Thus, our data demonstrate for the first time that in low noncytotoxic concentrations chemotherapeutic agents do not induce apoptosis of DCs, but directly enhance DC maturation and function. This suggests that modulation of human DCs by noncytotoxic concentrations of antineoplastic drugs, i.e. chemomodulation, might represent a novel approach for up-regulation of functional activity of resident DCs in the tumor microenvironment or improving the efficacy of DCs prepared ex vivo for subsequent vaccinations.

• cancer
• dendritic cells
• malignant melanoma
• immunotherapy
• tumour vaccines

• Cancer Vaccines/administration & dosage
• Cancer Vaccines/immunology
• Cancer Vaccines/therapeutic use
• Clinical Trials as Topic
• Dendritic Cells/immunology
• Humans
• Melanoma/drug therapy

• paclitaxel
• docetaxel
• cancer vaccine
• program death ligand
• dendritic cell vaccine

• Animals
• Antineoplastic Agents/administration & dosage
• Cancer Vaccines/administration & dosage
• Clinical Trials as Topic
• Combined Modality Therapy
• Humans
• Neoplasms/therapy

• Adult
• Cancer Vaccines/immunology
• Cancer Vaccines/therapeutic use
• Epitopes, T-Lymphocyte/immunology
• Female
• Human papillomavirus 16/immunology
• Humans
• Immunotherapy/methods
• Interferon-gamma/biosynthesis
• Middle Aged
• Oncogene Proteins, Viral/immunology
• Papillomavirus E7 Proteins
• Papillomavirus Infections/complications
• Papillomavirus Vaccines/immunology
• Papillomavirus Vaccines/therapeutic use
• Peptides/immunology
• Peptides/therapeutic use
• Repressor Proteins/immunology
• T-Lymphocytes/immunology
• Tumor Virus Infections/immunology
• Tumor Virus Infections/therapy
• Uterine Cervical Neoplasms/therapy
• Uterine Cervical Neoplasms/virology

Harnessing of the immune system by the development of ‘therapeutic’ vaccines, for the battle against cancer has been the focus of tremendous research efforts over the past two decades. As an illustration of the impressive amounts of data gathered over the past years, numerous antigens expressed on the surface of cancer cells, have been characterized. To this end, recent years research has focussed on characterization of antigens that play an important role for the growth and survival of cancer cells. Anti-apoptotic molecules like survivin that enhance the survival of cancer cells and facilitate their escape from cytotoxic therapies represent prime vaccination candidates. The characterization of a high number of tumor antigens allow the concurrent or serial immunological targeting of different proteins associated with such cancer traits. Moreover, while vaccination in itself is a promising new approach to fight cancer, the combination with additional therapy could create a number of synergistic effects. Herein we discuss the possibilities and prospects of vaccination when combined with other treatments. In this regard, cell death upon drug exposure may be immunogenic or non-immunogenic depending on the specific chemotherapeutics. Also, chemotherapy represents one of several options available for clearance of CD4⁺ Foxp3⁺ regulatory T cells. Moreover, therapies based on monoclonal antibodies may have synergistic potential in combination with vaccination, both when used for targeting of tumor cells and endothelial cells. The efficacy of therapeutic vaccination against cancer will over the next few years be studied in settings taking advantage of strategies in which vaccination is combined with other treatment modalities. These combinations should be based on current knowledge not only regarding the biology of the cancer cell per se, but also considering how treatment may influence the malignant cell population as well as the immune system.

• Antineoplastic Agents/immunology
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Cancer Vaccines/administration & dosage
• Cancer Vaccines/immunology
• Drug Resistance, Neoplasm/immunology
• Glioma/drug therapy
• Glioma/immunology
• Glioma/prevention & control
• Humans