• allogeneic dendritic cells
• ilixadencel
• tissue-resident CD8+ T-cells
• tumor-reactive CD8+ T-cells
• tumor-specific CD8+ T-cells
• α4-1BB therapy

• Animals
• Mice
• CD8-Positive T-Lymphocytes
• Administration, Cutaneous
• Killer Cells, Natural
• Adjuvants, Immunologic
• Dendritic Cells
• Hematopoietic Stem Cell Transplantation

• Animals
• Mice
• Anniversaries and Special Events
• Neoplasms/drug therapy
• Immunotherapy
• Tumor Necrosis Factor Receptor Superfamily, Member 9/therapeutic use
• CD8-Positive T-Lymphocytes
• Signal Transduction

Malignant cells are susceptible to viral infection and consequent cell death. Virus-induced cell death is endowed with features that are known to stimulate innate and adaptive immune responses. Thus danger signals emitted by cells succumbing to viral infection as well as viral nucleic acids are detected by specific receptors, and tumor cell antigens can be routed to professional antigen-presenting cells. The anticancer immune response triggered by viral infection is frequently insufficient to eradicate malignancy but may be further amplified. For this purpose, transgenes encoding cytokines as co-stimulatory molecules can be genetically engineered into viral vectors. Alternatively, or in addition, it is possible to use monoclonal antibodies that either block inhibitory receptors of immune effector cells, or act as agonists for co-stimulatory receptors. Combined strategies are based on the ignition of a local immune response at the malignant site plus systemic immune boosting. We have recently reported examples of this approach involving the Vaccinia virus or Semliki Forest virus, interleukin-12 and anti-CD137 monoclonal antibodies.

The CD137 receptor is expressed by activated antigen-specific T-cells. CD137⁺ T-cells were identified inside TILs and PBMCs of different tumor types and have proven to be the naturally occurring antitumor effector cells, capable of expressing a wide variability in terms of TCR specificity against both shared and neoantigenic tumor-derived peptides. The aim of this review is thus summarizing and highlighting their role as drivers of patients’ immune responses in anticancer therapies as well as their potential role in future and current strategies of immunotherapy.

The CD137 receptor (4-1BB, TNF RSF9) is an activation induced molecule expressed by antigen-specific T-cells. The engagement with its ligand, CD137L, is capable of increasing T-cell survival, proliferation, and cytokine production. This allowed to identify the CD137⁺ T-cells as the real tumor-specific activated T-cell population. In fact, these cells express various TCRs that are specific for a wide range of tumor-derived peptides, both shared and neoantigenic ones. Moreover, their prevalence in sites close to the tumor and their unicity in killing cancer cells both in vitro and in vivo, raised particular interest in studying their potential role in different strategies of immunotherapy. They indeed showed to be a reliable marker able to predict patient’s outcome to immune-based therapies as well as monitor their response. In addition, the possibility of isolating and expanding this population, turned promising in order to generate effector antitumor T-cells in the context of adoptive T-cell therapies. CD137-targeting monoclonal antibodies have already shown their antitumor efficacy in cancer patients and a number of clinical trials are thus ongoing to test their possible introduction in different combination approaches of immunotherapy. Finally, the intracellular domain of the CD137 receptor was introduced in the anti-CD19 CAR-T cells that were approved by FDA for the treatment of pediatric B-cell leukemia and refractory B-cell lymphoma.

• 4-1BB
• ACT
• CAR-T
• CD137
• CD137+ T-cells
• TILs
• biomarker
• immunotherapy
• monoclonal antibodies

• IL-12 plasmid
• PEG
• alkyl chains
• cholesterol
• cytotoxicity
• gene delivery
• polyamidoamine

The selective expression of CD137 on cells of the immune system (e.g., T and DC cells) and oncogenic cells in several types of cancer leads this molecule to be an attractive target to discover cancer immunotherapy. Therefore, specific antibodies against CD137 are being studied and developed aiming to activate and enhance anti-cancer immune responses as well as suppress oncogenic cells. Accumulating evidence suggests that anti-CD137 antibodies can be used separately to prevent tumor in some cases, while in other cases, these antibodies need to be co-administered with other antibodies or drugs/vaccines/regents for a better performance. Thus, in this work, we aim to update and discuss current knowledge about anti-cancer effects of anti-CD137 antibodies as mono- and combined-immunotherapies.

• CD137/4-1BB
• CD137L/4-1BBL
• anti-CD137 antibodies
• anti-CD137 antibody therapy
• cancer immunotherapies

• Animals
• Antineoplastic Agents, Immunological/pharmacology
• Antineoplastic Agents, Immunological/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Biomarkers
• Combined Modality Therapy
• Humans
• Immunotherapy
• Molecular Targeted Therapy/adverse effects
• Molecular Targeted Therapy/methods
• Neoplasms/drug therapy
• Neoplasms/immunology
• Neoplasms/metabolism
• Treatment Outcome
• Tumor Necrosis Factor Receptor Superfamily, Member 9/agonists
• Tumor Necrosis Factor Receptor Superfamily, Member 9/antagonists & inhibitors
• Tumor Necrosis Factor Receptor Superfamily, Member 9/metabolism

• Animals
• Antineoplastic Agents, Immunological/pharmacology
• Cell Line, Tumor
• Disease Progression
• Humans
• Immunophenotyping
• Interferon-gamma
• Lymphocytes, Tumor-Infiltrating/drug effects
• Lymphocytes, Tumor-Infiltrating/immunology
• Lymphocytes, Tumor-Infiltrating/metabolism
• Membrane Glycoproteins/antagonists & inhibitors
• Mice
• Myeloid-Derived Suppressor Cells/drug effects
• Myeloid-Derived Suppressor Cells/immunology
• Myeloid-Derived Suppressor Cells/metabolism
• Neoplasms/drug therapy
• Neoplasms/immunology
• Neoplasms/metabolism
• Neoplasms/pathology
• T-Lymphocytes/drug effects
• T-Lymphocytes/immunology
• T-Lymphocytes/metabolism
• Tumor Microenvironment/genetics
• Tumor Microenvironment/immunology

• I01 BX004069 BLRD VA
• P30 CA142543 NCI NIH HHS
• P50 CA196516 NCI NIH HHS
• R56 AI064927 NIAID NIH HHS

• T cells
• cancer immunotherapy
• cross-presentation
• cross-priming
• dendritic cells

Finding intracellular pathways and molecules that can prevent the proliferation of colon cancer cells can provide significant bases for developing treatments for this disease. Ostreolysin (Oly) is a protein found in the mushroom Pleurotus ostreatus, and we have produced a recombinant version of this protein (rOly).

We measured the viability of several colon cancer cells treated with rOly. Xenografts and syngeneic colon cancer cells were injected into in vivo mouse models, which were then treated with this recombinant protein.

rOly treatment induced a significant reduction in viability of human and mouse colon cancer cells. In contrast, there was no reduction in the viability of normal epithelial cells from the small intestine. In the search for cellular targets of rOly, we showed that it enhances the anti-proliferative activity of drugs targeting cellular tubulin. This was accompanied by a reduction in the weight and volume of tumours in mice injected with rOly as compared to their respective control mice in two in vivo models.

Our results advance the functional understanding of rOly as a potential anti-cancer treatment associated with pro-apoptotic activities preferentially targeting colon cancer cells.

• colon cancer
• fungal
• microtubule
• pro-apoptotic
• recombinant ostreolysin

• JNK/STAT3
• colon cancer
• leptin
• mitochondria
• obesity

• immune checkpoints
• immunogenic cell death
• melanoma
• senescence

• Animals
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Humans
• Immunologic Factors/therapeutic use
• Immunotherapy
• Neoplasms/immunology
• Neoplasms/therapy

• I01 BX002301 BLRD VA
• K24 CA172355 NCI NIH HHS
• IK6 BX005225 BLRD VA
• K12 CA090625 NCI NIH HHS
• R01 CA034590 NCI NIH HHS
• I01 BX000196 BLRD VA
• P30 CA068485 NCI NIH HHS
• R01 CA116021 NCI NIH HHS

• Cancer immunotherapy ⋅ CD137 (4-1BB) ⋅ Costimulation ⋅ K63-polyubiquitin⋅ TRAF-2

Immunotherapy is a rapidly expanding field of oncology aimed at targeting, not the tumor itself, but the immune system combating the cancerous lesion. Of the many approaches currently under study to boost anti-tumor immune responses; modulation of immune co-receptors on lymphocytes in the tumor microenvironment has thus far proven to be the most effective. Antibody blockade of the T cell co-inhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) has become the first FDA approved immune checkpoint blockade; however, tumor infiltrating lymphocytes express a diverse array of additional stimulatory and inhibitory co-receptors, which can be targeted to boost tumor immunity. Among these, the co-stimulatory receptor 4-1BB (CD137/TNFSF9) possesses an unequaled capacity for both activation and pro-inflammatory polarization of anti-tumor lymphocytes. While functional studies of 4-1BB have focused on its prominent role in augmenting cytotoxic CD8 T cells, 4-1BB can also modulate the activity of CD4 T cells, B cells, natural killer cells, monocytes, macrophages, and dendritic cells. 4-1BB’s expression on both T cells and antigen presenting cells, coupled with its capacity to promote survival, expansion, and enhanced effector function of activated T cells, has made it an alluring target for tumor immunotherapy. In contrast to immune checkpoint blocking antibodies, 4-1BB agonists can both potentiate anti-tumor and anti-viral immunity, while at the same time ameliorating autoimmune disease. Despite this, 4-1BB agonists can trigger high grade liver inflammation which has slowed their clinical development. In this review, we discuss how the underlying immunobiology of 4-1BB activation suggests the potential for therapeutically synergistic combination strategies in which immune adverse events can be minimized.

• 4-1BB
• CD137
• co-stimulation
• combination therapy
• immunotherapy

• Adoptive cell therapy
• CAR T cells
• Checkpoint blockade
• Costimulation
• Immunotherapy

Although considerable progress has been made in understanding how tumors evade immune surveillance, measures to counter the same have not kept pace with the advances made in designing effective strategies. 4-1BB (CD137; TNFRS9), an activation-induced costimulatory molecule, is an important regulator of immune responses. Targeting 4-1BB or its natural ligand 4-1BB ligand (4-1BBL) has important implications in many clinical conditions, including cancer. In-depth analysis revealed that 4-1BB-mediated anti-cancer effects are based on its ability to induce activation of cytotoxic T lymphocytes (CTL), and among others, high amounts of IFN-γ. In this review, we will discuss the various aspects of 4-1BB-mediated anti-tumor responses, the basis of such responses, and future directions. [BMB Reports 2014; 47(3): 122-129]

• Antibody
• CD137
• cyclophosphamide
• gemcitabine
• myeloid-derived suppressor cells

The endothelium is nowadays described as an entire organ that regulates various processes: vascular tone, coagulation, inflammation, and immune cell trafficking, depending on the vascular site and its specific microenvironment as well as on endothelial cell-intrinsic mechanisms like epigenetic changes. In this review, we will focus on the control of the adaptive immune response by the tumor vasculature. In physiological conditions, the endothelium acts as a barrier regulating cell trafficking by specific expression of adhesion molecules enabling adhesion of immune cells on the vessel, and subsequent extravasation. This process is also dependent on chemokine and integrin expression, and on the type of junctions defining the permeability of the endothelium. Endothelial cells can also regulate immune cell activation. In fact, the endothelial layer can constitute immunological synapses due to its close interactions with immune cells, and the delivery of co-stimulatory or co-inhibitory signals. In tumor conditions, the vasculature is characterized by an abnormal vessel structure and permeability, and by a specific phenotype of endothelial cells. All these abnormalities lead to a modulation of intra-tumoral immune responses and contribute to the development of intra-tumoral immunosuppression, which is a major mechanism for promoting the development, progression, and treatment resistance of tumors. The in-depth analysis of these various abnormalities will help defining novel targets for the development of anti-tumoral treatments. Furthermore, eventual changes of the endothelial cell phenotype identified by plasma biomarkers could secondarily be selected to monitor treatment efficacy.

• adaptive immunity
• endothelial cell
• immunological synapse
• lymphocyte infiltration
• tumor

Apolipoprotein A-I (Apo A-I) is a major component of high density lipoproteins (HDL) that transport cholesterol in circulation. We have constructed an expression plasmid encoding a chimeric molecule encompassing interleukin-15 (IL-15) and Apo A-I (pApo-hIL15) that was tested by hydrodynamic injections into mice and was co-administered with a plasmid encoding the sushi domain of IL-15Rα (pSushi) in order to enhance IL-15 trans-presentation and thereby bioactivity. The pharmacokinetics of the Apo A-I chimeric protein were much longer than non-stabilized IL-15 and its bioactivity was enhanced in combination with IL-15Rα Sushi. Importantly, the APO-IL-15 fusion protein was incorporated in part into circulating HDL. Liver gene transfer of these constructs increased NK and memory-phenotype CD8 lymphocyte numbers in peripheral blood, spleen and liver as a result of proliferation documented by CFSE dilution and BrdU incorporation. Moreover, the gene transfer procedure partly rescued the NK and memory T-cell deficiency observed in IL-15Rα^−/− mice. pApo-hIL15+ pSushi gene transfer to the liver showed a modest therapeutic activity against subcutaneously transplanted MC38 colon carcinoma tumors, that was more evident when tumors were set up as liver metastases. The improved pharmacokinetic profile and the strong biological activity of APO-IL-15 fusion protein holds promise for further development in combination with other immunotherapies.

• Animals
• Cell Line, Tumor
• Cell Proliferation
• Endothelial Cells/immunology
• Endothelial Cells/metabolism
• Female
• Immune System/immunology
• Immune System/metabolism
• Immunotherapy
• Melanoma, Experimental/immunology
• Melanoma, Experimental/metabolism
• Melanoma, Experimental/pathology
• Melanoma, Experimental/therapy
• Mice
• Models, Immunological
• T-Lymphocytes, Cytotoxic/immunology
• Tumor Necrosis Factor Receptor Superfamily, Member 9/metabolism

Interleukin-8 (IL-8, CXCL8) is readily produced by human malignant cells. Dendritic cells (DC) both produce IL-8 and express the IL-8 functional receptors CXCR1 and CXCR2. Most human colon carcinomas produce IL-8. IL-8 importance in malignancies has been ascribed to angiogeneis promotion.

IL-8 effects on human monocyte-derived DC biology were explored upon DC exposure to recombinant IL-8 and with the help of an IL-8 neutralizing mAb. In vivo experiments were performed in immunodeficient mice xenografted with IL-8-producing human colon carcinomas and comparatively with cell lines that do not produce IL-8. Allogenic T lymphocyte stimulation by DC was explored under the influence of IL-8. DC and neutrophil chemotaxis were measured by transwell-migration assays. Sera from tumor-xenografted mice contained increasing concentrations of IL-8 as the tumors progress. IL-8 production by carcinoma cells can be modulated by low doses of cyclophosphamide at the transcription level. If human DC are injected into HT29 or CaCo2 xenografted tumors, DC are retained intratumorally in an IL-8-dependent fashion. However, IL-8 did not modify the ability of DC to stimulate T cells. Interestingly, pre-exposure of DC to IL-8 desensitizes such cells for IL-8-mediated in vitro or in vivo chemoattraction. Thereby DC become disoriented to subsequently follow IL-8 chemotactic gradients towards malignant or inflamed tissue.

IL-8 as produced by carcinoma cells changes DC migration cues, without directly interfering with DC-mediated T-cell stimulation.

• T cell
• TNF-receptor
• combinational therapeutics
• costimulation
• cytotoxic T cell
• immunotherapy
• regulatory T cell

• cd137 (4-1bb)
• liver
• immunostimulatory monoclonal antibodies

• Amidinotransferases/immunology
• Amidinotransferases/metabolism
• Animals
• Antibodies, Monoclonal/administration & dosage
• CD8-Positive T-Lymphocytes/drug effects
• CD8-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/metabolism
• CD8-Positive T-Lymphocytes/pathology
• Cell Count
• Cell Line, Tumor
• Cell Movement/drug effects
• Colonic Neoplasms/immunology
• Colonic Neoplasms/pathology
• Colonic Neoplasms/therapy
• Immunotherapy
• Liver/drug effects
• Liver/immunology
• Liver/metabolism
• Liver/pathology
• Lymphocytes, Tumor-Infiltrating/immunology
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Neoplasm Transplantation
• Organ Specificity
• Receptors, Antigen, T-Cell, alpha-beta/genetics
• Receptors, Antigen, T-Cell, alpha-beta/metabolism
• Tumor Necrosis Factor Receptor Superfamily, Member 9/genetics
• Tumor Necrosis Factor Receptor Superfamily, Member 9/immunology

• 4-1BB Ligand/immunology
• CD8-Positive T-Lymphocytes/drug effects
• CD8-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/metabolism
• Cell Differentiation
• Cells, Cultured
• Cytotoxicity, Immunologic/drug effects
• Cytotoxicity, Immunologic/immunology
• Down-Regulation/drug effects
• Down-Regulation/immunology
• Fetal Blood/drug effects
• Fetal Blood/immunology
• Fetal Blood/metabolism
• Humans
• Immunologic Memory/immunology
• Interleukin-4/pharmacology
• Lymphocyte Activation/immunology
• NK Cell Lectin-Like Receptor Subfamily K
• Receptors, Immunologic/immunology
• Receptors, Natural Killer Cell
• Transforming Growth Factor beta1/pharmacology

• R01 HL56416 NHLBI NIH HHS
• P01 HL053586 NHLBI NIH HHS
• R01 HL67384 NHLBI NIH HHS
• P01 HL53586 NHLBI NIH HHS
• R01 HL067384 NHLBI NIH HHS
• R01 HL056416 NHLBI NIH HHS

Immunotherapy encompasses a variety of interventions and techniques with the common goal of eliciting tumor cell destructive immune responses. Colorectal carcinoma often presents as metastatic disease that impedes curative surgery. Novel strategies such as active immunization with dendritic cells (DCs), gene transfer of cytokines into tumor cells or administration of immunostimulatory monoclonal antibodies (such as anti-CD137 or anti-CTLA-4) have been assessed in preclinical studies and are at an early clinical development stage. Importantly, there is accumulating evidence that chemotherapy and immunotherapy can be combined in the treatment of some cases with colorectal cancer, with synergistic potentiation as a result of antigens cross-presented by dendritic cells and/or elimination of competitor or suppressive T lymphocyte populations (regulatory T-cells). However, genetic and epigenetic unstable carcinoma cells frequently evolve mechanisms of immunoevasion that are the result of either loss of antigen presentation, or an active expression of immunosuppressive substances. Some of these actively immunosuppressive mechanisms are inducible by cytokines that signify the arrival of an effector immune response. For example, induction of 2, 3 indoleamine dioxygenase (IDO) by IFNγ in colorectal carcinoma cells. Combinational and balanced strategies fostering antigen presentation, T-cell costimulation and interference with immune regulatory mechanisms will probably take the stage in translational research in the treatment of colorectal carcinoma.

• Colorectal carcinoma
• Immunotherapy
• Gene therapy
• Interleukin-12
• Dendritic cells
• CD137
• Indoleamine 2, 3 dioxygenase

• Animals
• Antibodies, Monoclonal/immunology
• Antibodies, Monoclonal/pharmacology
• CD11c Antigen/immunology
• CD4 Antigens/immunology
• CD4-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/immunology
• Immunization, Passive/methods
• Melanoma, Experimental/immunology
• Melanoma, Experimental/therapy
• Mice
• Mice, Inbred C57BL
• NK Cell Lectin-Like Receptor Subfamily K
• Receptors, Immunologic/immunology
• Receptors, Natural Killer Cell
• T-Lymphocytes, Cytotoxic/immunology
• Tumor Necrosis Factor Receptor Superfamily, Member 9/immunology

• R01EY013325 NEI NIH HHS

• Animals
• Female
• Genetic Vectors
• Male
• Mice
• Mice, Inbred C57BL
• Neoplasms, Experimental/virology
• Semliki forest virus/genetics
• Semliki forest virus/pathogenicity

• Antibodies, Monoclonal/immunology
• Antibodies, Monoclonal/therapeutic use
• Humans
• Immunity, Cellular
• Neoplasms/immunology
• Neoplasms/therapy

• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/radiotherapy
• Carcinoma, Hepatocellular/therapy
• Carcinoma, Hepatocellular/virology
• Humans
• Liver Neoplasms/genetics
• Liver Neoplasms/radiotherapy
• Liver Neoplasms/therapy
• Liver Neoplasms/virology

• 4-1BB Ligand/immunology
• 4-1BB Ligand/metabolism
• Animals
• Antibodies, Monoclonal/immunology
• Humans
• Protein Transport
• Signal Transduction/immunology

• Adenoviridae/genetics
• Adenoviridae/pathogenicity
• Adenovirus E1A Proteins/genetics
• Adenovirus E1A Proteins/metabolism
• Animals
• Antineoplastic Agents/pharmacology
• Breast Neoplasms/immunology
• Breast Neoplasms/pathology
• Breast Neoplasms/therapy
• CD40 Ligand/genetics
• Cancer Vaccines/administration & dosage
• Cancer Vaccines/immunology
• Cell Transplantation/methods
• Cytokines/metabolism
• Dendritic Cells/immunology
• Dendritic Cells/transplantation
• Female
• Fluorouracil/pharmacology
• Genetic Vectors
• Green Fluorescent Proteins/genetics
• Green Fluorescent Proteins/metabolism
• Humans
• Immunotherapy
• Mice
• Mice, Inbred BALB C
• Neoplasm Metastasis/immunology
• Neoplasm Metastasis/therapy
• T-Lymphocytes/immunology
• Tumor Cells, Cultured

• Adenocarcinoma/immunology
• Adenocarcinoma/prevention & control
• Adenocarcinoma/therapy
• Animals
• Cell Line, Tumor
• Colonic Neoplasms/immunology
• Colonic Neoplasms/prevention & control
• Colonic Neoplasms/therapy
• Genetic Therapy
• Genetic Vectors
• Immunity, Cellular/immunology
• Interleukin-12/genetics
• Interleukin-12/metabolism
• Mice
• Semliki forest virus
• T-Lymphocytes, Cytotoxic/immunology

• Angioplasty, Balloon, Coronary/adverse effects
• Animals
• Coronary Restenosis/genetics
• Coronary Restenosis/therapy
• Genetic Therapy/methods
• Humans
• Oligonucleotides, Antisense/administration & dosage
• Oligonucleotides, Antisense/genetics