Inhibition of interleukin-10 (IL-10) production from MOPC 315 tumor cells by IL-10 antisense oligodeoxynucleotides enhances cell-mediated immune responses

The focus of treating cancer with oncolytic viruses (OVs) has increasingly shifted towards achieving efficacy through the induction and augmentation of an antitumor immune response. However, innate antiviral responses can limit the activity of many OVs within the tumor and several immunosuppressive factors can hamper any subsequent antitumor immune responses. In recent decades, numerous small molecule compounds that either inhibit the immunosuppressive features of tumor cells or antagonize antiviral immunity have been developed and tested for. Here we comprehensively review small molecule compounds that can achieve therapeutic synergy with OVs. We also elaborate on the mechanisms by which these treatments elicit anti-tumor effects as monotherapies and how these complement OV treatment.

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Immunomodulating nano-adaptors potentiate antibody-based cancer immunotherapy

Nature Communications ◽

10.1038/s41467-021-21497-6 ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Cheng-Tao Jiang ◽

Kai-Ge Chen ◽

An Liu ◽

Hua Huang ◽

Ya-Nan Fan ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Cancer Immunotherapy ◽

Tumor Cells ◽

Noncovalent Interactions ◽

Killer Cell ◽

Antibody Immobilization ◽

Effector Cells ◽

Nanoparticle Surface

AbstractModulating effector immune cells via monoclonal antibodies (mAbs) and facilitating the co-engagement of T cells and tumor cells via chimeric antigen receptor- T cells or bispecific T cell-engaging antibodies are two typical cancer immunotherapy approaches. We speculated that immobilizing two types of mAbs against effector cells and tumor cells on a single nanoparticle could integrate the functions of these two approaches, as the engineered formulation (immunomodulating nano-adaptor, imNA) could potentially associate with both cells and bridge them together like an ‘adaptor’ while maintaining the immunomodulatory properties of the parental mAbs. However, existing mAbs-immobilization strategies mainly rely on a chemical reaction, a process that is rough and difficult to control. Here, we build up a versatile antibody immobilization platform by conjugating anti-IgG (Fc specific) antibody (αFc) onto the nanoparticle surface (αFc-NP), and confirm that αFc-NP could conveniently and efficiently immobilize two types of mAbs through Fc-specific noncovalent interactions to form imNAs. Finally, we validate the superiority of imNAs over the mixture of parental mAbs in T cell-, natural killer cell- and macrophage-mediated antitumor immune responses in multiple murine tumor models.

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Natural Killer–Dendritic Cell Interactions in Liver Cancer: Implications for Immunotherapy

Cancers ◽

10.3390/cancers13092184 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2184

Author(s):

Valentina Cazzetta ◽

Sara Franzese ◽

Claudia Carenza ◽

Silvia Della Bella ◽

Joanna Mikulak ◽

...

Keyword(s):

Liver Cancer ◽

Immune Responses ◽

Nk Cells ◽

Natural Killer ◽

Tumor Cells ◽

Primary Liver Cancer ◽

Circulating Antigens ◽

Direct Cytotoxicity ◽

Immune Changes

Natural killer (NK) and dendritic cells (DCs) are innate immune cells that play a crucial role in anti-tumor immunity. NK cells kill tumor cells through direct cytotoxicity and cytokine secretion. DCs are needed for the activation of adaptive immune responses against tumor cells. Both NK cells and DCs are subdivided in several subsets endowed with specialized effector functions. Crosstalk between NK cells and DCs leads to the reciprocal control of their activation and polarization of immune responses. In this review, we describe the role of NK cells and DCs in liver cancer, focusing on the mechanisms involved in their reciprocal control and activation. In this context, intrahepatic NK cells and DCs present unique immunological features, due to the constant exposure to non-self-circulating antigens. These interactions might play a fundamental role in the pathology of primary liver cancer, namely hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Additionally, the implications of these immune changes are relevant from the perspective of improving the cancer immunotherapy strategies in HCC and ICC patients.

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Biomarkers of Radiotherapy-Induced Immunogenic Cell Death

Cells ◽

10.3390/cells10040930 ◽

2021 ◽

Vol 10 (4) ◽

pp. 930

Author(s):

Rianne D. W. Vaes ◽

Lizza E. L. Hendriks ◽

Marc Vooijs ◽

Dirk De Ruysscher

Keyword(s):

Cell Death ◽

Immune Responses ◽

Tumor Cells ◽

Immunogenic Cell Death ◽

Type I ◽

Future Studies ◽

Regulated Cell Death ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns ◽

Potential Biomarkers

Radiation therapy (RT) can induce an immunogenic variant of regulated cell death that can initiate clinically relevant tumor-targeting immune responses. Immunogenic cell death (ICD) is accompanied by the exposure and release of damage-associated molecular patterns (DAMPs), chemokine release, and stimulation of type I interferon (IFN-I) responses. In recent years, intensive research has unraveled major mechanistic aspects of RT-induced ICD and has resulted in the identification of immunogenic factors that are released by irradiated tumor cells. However, so far, only a limited number of studies have searched for potential biomarkers that can be used to predict if irradiated tumor cells undergo ICD that can elicit an effective immunogenic anti-tumor response. In this article, we summarize the available literature on potential biomarkers of RT-induced ICD that have been evaluated in cancer patients. Additionally, we discuss the clinical relevance of these findings and important aspects that should be considered in future studies.

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Differential Activation of CD8+Tumor-Specific Tc1 and Tc2 Cells by an IL-10-Producing Murine Plasmacytoma

Developmental Immunology ◽

10.1155/1998/93545 ◽

1998 ◽

Vol 6 (3-4) ◽

pp. 331-342 ◽

Cited By ~ 1

Author(s):

Christoph Specht ◽

Hans-Gerd Pauels ◽

Christian Becker ◽

Eckehart Kölsch

Keyword(s):

T Cells ◽

Immune Responses ◽

Tumor Cells ◽

T Cell Subsets ◽

Early Stages ◽

Specific Tolerance

The involvement of counteractiveCD8+T-cell subsets during tumor-specific immune responses was analyzed in a syngeneic murine plasmacytoma model.CD8+Tc cells against the immunogenic IL-10-producing BALB/c plasmacytoma ADJ-PC-5 can be easily induced by immunization of BALB/c mice with X-irradiated ADJ-PC-5 tumor cellsin vivoandin vitro. However, the failure of recipient mice to mount a protective Tc response against the tumor during early stages of a real or simulated tumor growth is not due to immunological ignorance, but depends on the induction of tumor-specific tolerance, involving a population of tumorinducedCD8+T cells that are able to inhibit the generation of tumor-specific Tc cells in a primary ADJ-PC-5-specific MLTC, using IFN-γas a suppressive factor. Whereas most longterm cultivated CD8+ADJ-PC-5-specific Tc lines produce type-1 cytokines on stimulation, at least two of them, which were derived from a primary MLTC, display a type-2 cytokine spectrum. Furthermore, the primaryin vitroTc response against ADJ-PC-5 cells shows characteristics of a Tc2 response. The Tc response is strictly depending on tumor-derived IL-10.CD8+Tc cells that are induced in a primary MLTC do not produce IFN-γ, and the tumor-specific Tc response is enhanced by IL-4 but suppressed by IFN-γor IL-12. In contrast, ADJ-PC- 5-specificCD8+Tc cells from immunized mice are IFN-γproducing Tc1 cells. Since the primaryin vitroTc response against the tumor is suppressed even by the smallest numbers of irradiated ADJ-PC-5-specific Tc1 cells via IFN-γthese Tc1 cells behave similar to the suppressiveCD8+T cells that are induced during early stages of ADJ-PC-5 tumorigenesis.

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Immunosensitization of Tumor Cells to Dendritic Cell-Activated Immune Responses with the Proteasome Inhibitor Bortezomib (PS-341, Velcade)

The Journal of Immunology ◽

10.4049/jimmunol.176.8.4757 ◽

2006 ◽

Vol 176 (8) ◽

pp. 4757-4765 ◽

Cited By ~ 44

Author(s):

Lana Y. Schumacher ◽

Dan D. Vo ◽

Hermes J. Garban ◽

Begoña Comin-Anduix ◽

Sharla K. Owens ◽

...

Keyword(s):

Dendritic Cell ◽

Immune Responses ◽

Tumor Cells ◽

Proteasome Inhibitor

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Efficient migration of dendritic cells toward lymph node chemokines and induction of TH1 responses require maturation stimulus and apoptotic cell interaction

Blood ◽

10.1182/blood-2004-10-3991 ◽

2005 ◽

Vol 106 (5) ◽

pp. 1734-1741 ◽

Cited By ~ 26

Author(s):

Nicolas Bertho ◽

Henri Adamski ◽

Louis Toujas ◽

Martine Debove ◽

Jean Davoust ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Lymph Node ◽

Immune Responses ◽

Tumor Cells ◽

Apoptotic Cell ◽

Apoptotic Cells ◽

Naive T Cells ◽

Naïve T Cells ◽

Tnf Α

Abstract Dendritic cells (DCs) have the unique ability to initiate primary immune responses, and they can be conditioned for vaccinal purposes to present antigens after the engulfment of apoptotic cells. To recruit the rare antigen-specific naive T cells, DCs require a maturation step and subsequent transport toward lymph node (LN). To date, prostaglandin E2 (PGE2) is the best-characterized compound inducing this LN-directed migration in vitro, but PGE2 may skew the immune responses in a TH2 direction. We demonstrate here that on incubation with apoptotic tumor cells and tumor necrosis factor-α (TNF-α) or lipopolysaccharide (LPS), human monocyte-derived DCs become fully mature and acquire high migratory capacities toward LN-directing chemokines. The migration of TNF-α-treated DCs occurs only after cotreatment with apoptotic cells but not with necrotic cells. DC migration requires CD36 expression and incubation with apoptotic cells in the presence of heat-labile serum components. Moreover, on treatment with apoptotic cells and LPS, the migrating DCs are able to recruit naive T cells to generate TH1 immune responses. Our results show that the cotreatment of DCs with apoptotic tumor cells and inflammatory signals is promising for the design of an antitumoral DC-based vaccine. (Blood. 2005;106:1734-1741)

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EFFICIENCY OF THE FORMATION OF ANTITUMOR IMMUNE RESPONSES IN THE SYSTEM OF PREVENTIVE VACCINATION OF MICE WITH TESTICULAR ANTIGENS

Medical Immunology (Russia) ◽

10.15789/1563-0625-eot-2299 ◽

2021 ◽

Vol 23 (4) ◽

pp. 665-670

Author(s):

A. B. Dorzhieva ◽

T. S. Khabalova ◽

Yu. E. Androsova ◽

E. A. Kaschenko ◽

I. P. Ivanova ◽

...

Keyword(s):

Immune Responses ◽

Tumor Cells ◽

T Regulatory Cells ◽

Specific Method ◽

Large Set ◽

Chemotherapeutic Drugs ◽

Regulatory Cells ◽

Biochemical Processes ◽

Preventive Vaccination ◽

Experimental Group

Аppearance of a malignant tumor is associated with impaired mechanisms of proliferation, differentiation, apoptosis ability. However, these changes are not enough for immune system to recognize and destroy mutated cells. Weak immunogenicity of tumor-associated antigens (TAA) and the insufficiency of co-stimulating molecules on the surface of tumor cells is a reason for this phenomenon Since biochemical processes of tumor cells and healthy tissue cells are identical, therefore creation of effective chemotherapeutic drugs is limited not by selectivity of their action. So antitumor vaccination is the most effective specific method for both preventing recurrence of a disease and a therapeutic treatment tool in oncology. Xenogeneic proteins are highly immunogenic and effective in breaking immune tolerance to human analogs. In our work, we used sheep testicular AG as a source xenogenic TAAs. Sheep testicles contain a large set of TAAs. Experimental mice were immunized with type liposomal testicular vaccine from sheep, one month after vaccination, to induce tumor growth, cells of carcinoma LLC were implanted in mouse. The life expectancy of the experimental group of mice was 2 times higher compared to the syngenetic control and 20% of them did not develop the tumor at all. In the spleen of mice who did not have tumors after pre-vaccination sheep liposomal testicular AG, T-regulatory cells and T-memory cells were measured. We found a credible decrease in both naive Treg (CD4+CD25+), activated (CD4+CD25+FoxP3+) and both T-memory (CD4+CD44+) and central memory (CD4+CD44+CD62L+) in spleen pre-vaccination mice with compared to the contral intact spleen. Content of IFNg and IL-10 in supernatants of mouse slenocytes derived from vaccinated mice with no tumors was investigated and showed a reliable decrease in the amount of IL-10, but not IFNg. We believe that immunization with xenogenic tumor AGs can lead to the formation of a protective antitumor response.

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Engineering Tumor Cells with Tumor Necrosis Factor α (TNF-α) or CD40 Ligand (CD40L) Genes Induce Anti-tumor Immune Responses

International Journal of Peptide Research and Therapeutics ◽

10.1007/s10989-018-9687-8 ◽

2018 ◽

Vol 25 (2) ◽

pp. 427-436

Author(s):

Saeed Daneshmandi ◽

Somayeh Shahrokhi

Keyword(s):

Tumor Necrosis Factor ◽

Immune Responses ◽

Tumor Cells ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Cd40 Ligand ◽

Tnf Α ◽

Factor Α ◽

Necrosis Factor

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LS1 PRACTICAL APPLICATION AND UNDERLYING BIOLOGY OF TUMOR TREATING FIELDS

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz039.000 ◽

2019 ◽

Vol 1 (Supplement_2) ◽

pp. ii1-ii1

Author(s):

Daniela Bota

Keyword(s):

Immune Responses ◽

Tumor Cells ◽

Critical Role ◽

High Mobility ◽

Standard Of Care ◽

Clinical Results ◽

Phase Iii ◽

Tumor Treating Fields ◽

Standard Of Care Treatment ◽

Stress Signals

Abstract Glioblastoma (GBM) is the most common and most aggressive form of brain cancer in adults. For decades, the mainstay of therapeutic intervention was based on surgical resection (when safely feasible), followed by radiotherapy (RT). In 2005, data from the landmark EORTC-NCIC trial changed the standard of care treatment for GBM. This phase III trial demonstrated a survival advantage for concomitant and adjuvant temozolomide (TMZ) chemotherapy when added to the standard course of radiation. In the group of patients assigned to radiation plus TMZ, median survival improved from 12.1 months (radiotherapy alone) to 14.6 months, but all the patient finally relapsed on TMZ. In 2015, Tumor Treating Fields (TTF, Optune) became the first FDA-approved device for the treatment of for newly diagnosed GBM. This approval was based on the EF-14 clinical trial results, in which nearly half of the patients treated with Optune in combination with maintenance temozolomide (TMZ) were alive at 2 years compared with 31% of people on TMZ alone. Optune utilize the natural electrical properties of dividing cancer cells to disrupt mitosis and provide continuous antimitotic action against progression of GBM. TTF-treated tumor cells can exit the process of mitosis aberrantly and release cellular stress signals, such as the endoplasmic reticulum chaperonin calreticulin (CRT) and high mobility group box 1 protein (HMGB1). CRT is important to induce antitumor immune responses because CRT inhibition decreases immunogenicity. HMGB1, an endogenous chromatin-associated protein released from dying tumor cells, also plays a critical role in the activation of HMGB1-mediated toll-like receptor 2 (TLR2) immune signaling. The presence of those signals may facilitate immune activation, and immunogenic induced cell death, and eventually result in tumor destruction. In this presentation, Daniela Bota, MD, PhD, will review the clinical results of Optune in the treatment of GBM, and will discuss the novel biological mechanisms underlying the effects of Optune in controlling tumor growth and promoting the immune responses in GBM.

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