• Nanocancer
• colorectal
• nanoparticles
• nanovaccines

• cancer
• dendritic cell
• immunotherapy
• vaccine

• gold nanoparticles
• hyperthermia
• photothermal therapy
• temperature monitoring
• thermotolerance

• Humans
• Phototherapy/methods
• Hyperthermia, Induced/methods
• Heating
• Nanostructures
• Neoplasms/therapy
• Cell Line, Tumor
• Nanoparticles

• DP1 OD000798 NIH HHS
• R01 CA138527 NCI NIH HHS
• DP1 OD000798 ODCDC CDC HHS

• Cell fusion
• Dendritic cells (DC)
• Extraction of Hsp70 peptide complexes (Hsp70.PC)
• Heat shock proteins70 (Hsp70)
• Tumor vaccine

• 4-1BBL
• Anti-PD1 drug
• Anti-tumor immunotherapy
• CEACAM6
• Colorectal cancer
• Genetic vaccine

• cancer
• cell biology

Dendritic cells (DCs) are immune specialized cells playing a critical role in promoting immune response against antigens, and may represent important targets for therapeutic interventions in cancer. DCs can be stimulated ex vivo with pro-inflammatory molecules and loaded with tumor-specific antigen(s). Protocols describing the specific details of DCs vaccination manufacturing vary widely, but regardless of the employed protocol, the DCs vaccination safety and its ability to induce antitumor responses is clearly established. Many years of studies have focused on the ability of DCs to provide overall survival benefits at least for a selection of cancer patients. Lessons learned from early trials lead to the hypothesis that, to improve the efficacy of DCs-based immunotherapy, this should be combined with other treatments. Thus, the vaccine’s ultimate role may lie in the combinatorial approaches of DCs-based immunotherapy with chemotherapy and radiotherapy, more than in monotherapy. In this review, we address some key questions regarding the integration of DCs vaccination with multimodality therapy approaches for cancer treatment paradigms.

• adjuvant therapy
• cancer
• dendritic cells
• immunotherapy

• Adjuvants, Immunologic/therapeutic use
• Animals
• Antigens, Neoplasm/immunology
• Cancer Vaccines/immunology
• Cancer Vaccines/therapeutic use
• Combined Modality Therapy/methods
• Dendritic Cells/immunology
• Humans
• Immune Checkpoint Inhibitors/therapeutic use
• Immunotherapy, Adoptive/methods
• Neoplasms/drug therapy
• Neoplasms/immunology
• Neoplasms/radiotherapy
• Progression-Free Survival
• Tumor Escape/drug effects
• Tumor Escape/radiation effects

• CGGA
• TCGA
• biomarker
• immune infiltration
• low grade glioma

In addition to exerting several essential house-keeping activities in the cell, heat shock proteins (HSPs) are crucial players in a well-structured molecular program activated in response to stressful challenges. Among the different activities carried out by HSPs during emergency, they reach the extracellular milieu, from where they scout the surroundings, regulate extracellular protein activity and send autocrine and paracrine signals. Cancer cells permanently experience stress conditions due to their altered equilibrium and behaviour, and constantly secrete heat shock proteins as a result. Other than supporting anti-tumour immunity, extracellular heat shock proteins (eHSPs), can also exacerbate cancer cell growth and malignancy by sustaining different cancer hallmarks. eHSPs are implicated in extracellular matrix remodelling, resistance to apoptosis, promotion of cell migration and invasion, induction of epithelial to mesenchymal transition, angiogenesis and activation of stromal cells, supporting ultimately, metastasis dissemination. A broader understanding of eHSP activity and contribution to tumour development and progression is leading to new opportunities in the diagnosis and treatment of cancer.

• Cancer hallmarks
• Chaperones
• Extracellular
• Heat shock proteins
• Tumour microenvironment

Heat shock proteins 90 kDa (Hsp90s) were originally identified as stress-responsive proteins and described to participate in several homeostatic processes. Additionally, extracellular Hsp90s have the ability to bind to surface receptors and activate cellular functions related to immune response (cytokine secretion, cell maturation, and antigen presentation), making them very attractive to be studied as immunomodulators. In this context, Hsp90s are proposed as new adjuvants in the design of novel vaccine formulations that require the induction of a cell-mediated immune response to prevent infectious diseases. In this review, we summarized the adjuvant properties of Hsp90s when they are either alone, complexed, or fused to a peptide to add light to the knowledge of Hsp90s as carriers and adjuvants in the design of vaccines against infectious diseases. Besides, we also discuss the mechanisms by which Hsp90s activate and modulate professional antigen-presenting cells.

• GRP94
• Hsp90
• MHC class I
• carrier
• chaperones
• cross-presentation
• gp96
• re-presentation

Molecular chaperones are a set of conserved proteins that have evolved to assist the folding of many newly synthesized proteins by preventing their misfolding under conditions such as elevated temperatures, hypoxia, acidosis and nutrient deprivation. Molecular chaperones belong to the heat shock protein (HSP) family. They have been identified as important participants in immune functions including antigen presentation, immunostimulation and immunomodulation, and play crucial roles in metabolic rewiring and epigenetic circuits. Growing evidence has accumulated to indicate that metabolic pathways and their metabolites influence the function of immune cells and can alter transcriptional activity through epigenetic modification of (de)methylation and (de)acetylation. However, whether molecular chaperones can regulate metabolic programs to influence immune activity is still largely unclear. In this review, we discuss the available data on the biological function of molecular chaperones to immune responses during inflammation, with a specific focus on the interplay between molecular chaperones and metabolic pathways that drive immune cell fate and function.

• environmental stress
• epigenetics
• heat shock proteins
• immune responses
• immunometabolism
• molecular chaperones

• EGFR
• HSP
• NSCLC
• biomarker
• diagnosis
• immunotherapy
• prognosis

• Animals
• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/metabolism
• Heat-Shock Proteins/metabolism
• Humans
• Lung Neoplasms/diagnosis
• Lung Neoplasms/metabolism

• HSF1
• HSF1 expression in cancer
• HSF1 in cancer
• HSPs
• HSR
• cancer
• cancer therapy
• heat shock factor 1
• heat shock proteins
• heat shock response
• metastasis
• molecular chaperones
• tumorigenesis

• Animals
• Cell Transformation, Neoplastic/metabolism
• Cell Transformation, Neoplastic/pathology
• Heat Shock Transcription Factors/genetics
• Heat Shock Transcription Factors/metabolism
• Humans
• Molecular Chaperones/genetics
• Molecular Chaperones/metabolism
• Molecular Targeted Therapy
• Morbidity
• Neoplasms/epidemiology
• Neoplasms/genetics
• Neoplasms/metabolism

• R01 CA176326 NCI NIH HHS

Heat shock protein (HSP) synthesis is switched on in a remarkably wide range of tumor cells, in both experimental animal systems and in human cancer, in which these proteins accumulate in high levels. In each case, elevated HSP concentrations bode ill for the patient, and are associated with a poor outlook in terms of survival in most cancer types. The significance of elevated HSPs is underpinned by their essential roles in mediating tumor cell intrinsic traits such as unscheduled cell division, escape from programmed cell death and senescence, de novo angiogenesis, and increased invasion and metastasis. An increased HSP expression thus seems essential for tumorigenesis. Perhaps of equal significance is the pronounced interplay between cancer cells and the tumor milieu, with essential roles for intracellular HSPs in the properties of the stromal cells, and their roles in programming malignant cells and in the release of HSPs from cancer cells to influence the behavior of the adjacent tumor and infiltrating the normal cells. These findings of a triple role for elevated HSP expression in tumorigenesis strongly support the targeting of HSPs in cancer, especially given the role of such stress proteins in resistance to conventional therapies.

• Hsp70
• Hsp90
• cancer
• chaperome
• extracellular HSPs
• heat shock proteins
• molecular chaperones
• proteotoxic stress
• stress proteins in cancer
• tumor signaling

• Cancer stem cells
• Cisplatin
• Dendritic cells
• Immunotherapy
• Interferon gamma
• Solid Ehrlich carcinoma
• p53

• Animals
• Antineoplastic Agents/immunology
• Biomarkers, Tumor/immunology
• Cancer Vaccines/immunology
• Cell Line, Tumor
• Dendritic Cells/immunology
• Disease Models, Animal
• Drug Resistance, Neoplasm/immunology
• Female
• Immunotherapy/methods
• Interferon-gamma/immunology
• Mice
• Neoplasms/immunology
• Neoplasms/therapy
• Neoplastic Stem Cells/immunology
• Survival Rate
• Tumor Suppressor Protein p53/immunology
• Up-Regulation/immunology

• Sca-1
• genotoxic stress
• radiation bystander effect
• radiation therapy
• responses to cancer therapy

• Aldehyde Dehydrogenase 1 Family
• Animals
• Antigens, Ly/analysis
• Antigens, Ly/genetics
• Cell Line, Tumor
• Cell Movement/radiation effects
• DNA Damage/radiation effects
• Female
• Gene Expression Regulation, Neoplastic/radiation effects
• Isoenzymes/analysis
• Isoenzymes/genetics
• Mammary Neoplasms, Animal/genetics
• Mammary Neoplasms, Animal/pathology
• Mammary Neoplasms, Animal/radiotherapy
• Membrane Proteins/analysis
• Membrane Proteins/genetics
• Mice
• Mice, Inbred C57BL
• Neoplasm Metastasis/genetics
• Neoplasm Metastasis/pathology
• Retinal Dehydrogenase/analysis
• Retinal Dehydrogenase/genetics

• R01 CA047407 NCI NIH HHS
• R01 CA119045 NCI NIH HHS
• R01 CA176326 NCI NIH HHS

• Cell fusion
• Dendritic cells (DC)
• Extraction of Hsp70 peptide complexes (Hsp70.PC)
• Heat shock proteins70 (Hsp70)
• Tumor vaccine

• Breast Neoplasms/metabolism
• Breast Neoplasms/therapy
• Cancer Vaccines/immunology
• Cell Fusion/methods
• Dendritic Cells
• Female
• HSP70 Heat-Shock Proteins/immunology
• Humans
• Immunotherapy
• Neoplasm Proteins/immunology
• Ovarian Neoplasms/metabolism
• Ovarian Neoplasms/therapy

• Cancer immunotherapy
• Cellular vaccine
• DNA vaccine
• Heat shock protein

• 4-1BBL
• CEACAM6
• colorectal cancer
• recombinant attenuated Salmonella
• tumor-infiltrating lymphocytes
• vaccine

The incidence of colorectal cancer (CRC) is on the rise. Furthermore, late-stage diagnoses and limited efficacious treatment options make CRC a complex clinical challenge. Therefore, a new therapeutic regimen with a completely novel therapeutic mechanism is necessary for CRC. In the present study, the therapeutic efficacy of oncolytic herpes simplex virus type 2 (oHSV2) in CRC was assessed in vitro and in vivo. oHSV2 is an oncolytic agent derived from herpes simplex virus type 2 that encodes granulocyte-macrophage colony-stimulating factor.

We investigated the cytopathic effects of oHSV2 in CRC cell lines using the MTT assay. Then, cell cycle progression and apoptosis of oHSV2 were examined by flow cytometry. We generated a model of CRC with mouse CRC cell CT26 in BALB/c mice. The antitumor effects and adaptive immune response of oHSV2 were assessed in tumor-bearing mice. The therapeutic efficacy of oHSV2 was compared with the traditional chemotherapeutic agent, 5-fluorouracil.

The in vitro data showed that oHSV2 infected the CRC cell lines successfully and that the tumor cells formed a significant number of syncytiae postinfection. The oHSV2 killed cancer cells independent of the cell cycle and mainly caused tumor cells necrosis. The in vivo results showed that oHSV2 significantly inhibited tumor growth and prolonged survival of tumor-bearing mice without weight loss. With virus replication, oHSV2 not only resulted in a reduction of myeloid-derived suppressor cells and regulatory T cells in the spleen, but also increased the number of mature dendritic cells in tumor-draining lymph nodes and the effective CD4⁺T and CD8⁺T-cells in the tumor microenvironment.

Our study provides the first evidence that oHSV2 induces cell death in CRC in vitro and in vivo. These findings indicate that oHSV2 is an effective therapeutic cancer candidate that causes an oncolytic effect and recruits adaptive immune responses for an enhanced therapeutic impact, thus providing a potential therapeutic tool for treatment of CRC.

• colorectal cancer
• gene therapy
• granulocyte
• herpes simplex virus type 2
• immunotherapy
• macrophage colony-stimulating factor
• oncolytic virus

• Hsps
• alloimmunity
• dendritic cells
• immune regulation
• transplantation

• Disease relevance
• Function
• Hsp70
• Inhibitors
• Regulation
• Structure
• Therapeutic implications

• Carcinoma/genetics
• Carcinoma/pathology
• Cell Proliferation/genetics
• Cellular Senescence/genetics
• HSP70 Heat-Shock Proteins/genetics
• Humans
• Immunity, Innate/genetics
• Molecular Chaperones/genetics
• Multiprotein Complexes/genetics
• Protein Aggregates/genetics
• Protein Folding

Extracellular heat-shock proteins (HSPs) interact with the immune system in a very complex manner. Many such HSPs exert powerful effects on the immune response, playing both stimulatory and regulatory roles. However, the influence of the HSPs on immunity appears to be positive or negative in nature – rarely neutral. Thus, the HSPs can act as dominant antigens and can comprise key components of antitumor vaccines. They can also function as powerful immunoregulatory agents and, as such, are employed to treat inflammatory diseases or to extend the lifespan of tissue transplants. Small modifications in the cellular milieu have been shown to flip the allegiances of HSPs from immunoregulatory agents toward a potent inflammatory alignment. These mutable properties of HSPs may be related to the ability of these proteins to interact with multiple receptors often with mutually confounding properties in immune cells. Therefore, understanding the complex immune properties of HSPs may help us to harness their potential in treatment of a range of conditions.

• heat
• immunity
• immunosuppression
• protein
• receptors
• scavenger
• shock
• surface

In previous study the streptavidin interleukin-2 (SA-IL-2)-modified MB49 vaccine was effective against bladder cancer in a mouse model. However, a small portion of tumors regrew because the vaccine could not eliminate MB49 bladder cancer stem cells (MCSCs). Accordingly, we developed a SA-IL-2-modified MCSCs vaccine and evaluated its antitumor effects.

MCSCs were isolated and identified in cancer stem cells (CSCs) characters, with high expression of CSCs markers, higher resistance to chemotherapy, greater migration in vitro, and stronger tumorigenicity in vivo. The SA-IL-2 MCSCs vaccine was prepared and its bioactivity was evaluated. The protective, therapeutic, specific and memory immune response in animal experiments were designed to identify whether the vaccine elicited antitumor immunity and acted against metastatic bladder cancer.

MCSCs had higher level of CD133 and CD44, less susceptibility to chemotherapy, more pronounced migration and greater tumorigenic ability. The successfully prepared SA-IL-2 MCSCs vaccine inhibited the tumor volume and prolonged mice survival in animal experiments. The expression of IgG, the population of dendritic cells, CD8⁺ and CD4⁺ T cells were highest in the experimental group than in the four control groups.

The SA-IL-2 MCSCs vaccine induced an antitumor immune response and was used to eliminate MCSCs to prevent tumor regrowth.

• cancer vaccines
• dendritic cell
• dendritic cell–tumor fusion cell
• immunogenicity
• whole tumor cell

• Animals
• Cancer Vaccines/therapeutic use
• Combined Modality Therapy/methods
• Humans
• Mice
• Neoplasms/prevention & control
• Neoplasms/radiotherapy

• R21 CA162235 NCI NIH HHS
• Z01 BC010661-03 Intramural NIH HHS
• Z01 BC010975-01 Intramural NIH HHS
• R21CA162235 NCI NIH HHS

• abscopal effect
• annexin A5
• dendritic cell
• heat shock protein 70
• high-mobility group box protein 1
• immunogenic tumor cell death
• immunotherapy
• radiotherapy
• survivin
• vaccination

• radiotherapy
• immune therapy
• immunogenic tumor cell death
• damage-associated molecular patterns
• dendritic cell
• citim 2013

• Animals
• Cancer Vaccines/therapeutic use
• Combined Modality Therapy/methods
• DNA Damage
• Humans
• Immunologic Factors/immunology
• Immunotherapy/methods
• Necrosis
• Neoplasms/immunology
• Neoplasms/therapy
• Phenotype
• Radiation, Ionizing
• Radiotherapy/methods

The incidence of colorectal cancer (CRC) is on the rise, and the prognosis for patients with recurrent or metastatic disease is extremely poor. Although chemotherapy and radiation therapy can improve survival rates, it is imperative to integrate alternative strategies such as immunotherapy to improve outcomes for patients with advanced CRC. In this review, we will discuss the effect of immunotherapy for inducing cytotoxic T lymphocytes and the major immunotherapeutic approaches for CRC that are currently in clinical trials, including peptide vaccines, dendritic cell-based cancer vaccines, whole tumor cell vaccines, viral vector-based cancer vaccines, adoptive cell transfer therapy, antibody-based cancer immunotherapy, and cytokine therapy. The possibility of combination therapies will also be discussed along with the challenges presented by tumor escape mechanisms.

• Colorectal cancer
• Cytotoxic T lymphocyte
• Dendritic cell
• Immunotherapy
• Vaccine

• Animals
• Antibodies/therapeutic use
• Antineoplastic Agents/therapeutic use
• Cancer Vaccines/therapeutic use
• Colorectal Neoplasms/immunology
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/therapy
• Cytokines/therapeutic use
• Humans
• Immunotherapy/methods
• Immunotherapy, Adoptive
• Lymphocytes, Tumor-Infiltrating/drug effects
• Lymphocytes, Tumor-Infiltrating/immunology
• Lymphocytes, Tumor-Infiltrating/pathology
• Treatment Outcome
• Tumor Escape/drug effects