Laser-Ignited Lipid Peroxidation Nanoamplifiers for Strengthening Tumor Photodynamic Therapy Through Aggravating Ferroptotic Propagation and Sustainable High Immunogenicity.

Photodynamic therapy (PDT) is extensively investigated for tumor therapy in the clinic. However, the efficacy of PDT is severely limited by the tissue penetrability of light, short effective half-life and radius of reactive oxygen species (ROS), and the weak immunostimulatory effect. In this study, a glutathione (GSH)-activatable nano-photosensitizer is developed to load with arachidonic acid (AA) and camouflage by erythrocyte membrane, which serves as a laser-ignited lipid peroxidation nanoamplifier (MAR). The photosensitive effect of MAR is recovered accompanied by the degradation in the tumor microenvironment and triggers the peroxidation of AA upon laser excitation. Interestingly, it aggravates the propagation of ferroptosis among cancer cells by driving the continuous lipid peroxidation chain reactions with the participation of the degradation products, ferrous ions (Fe2+), and AA. Consequently, even the deep-seated tumor cells without illumination also undergo ferroptosis owing to the propagation of ferroptotic signal. Moreover, the residual tumor cells undergoing ferroptosis still maintain high immunogenicity after PDT, thus continuously triggering sufficient tumor-associated antigens (TAAs) release to remarkably promote the anti-tumor immune response. Therefore, this study will provide a novel "all-in-one" nano-photosensitizer that not only amplifies the damaging effect and expands the effective range of PDT but also improves the immunostimulatory effect after PDT.

PD-L1 siRNA hitched polyethyleneimine-elastase constituting nanovesicle induces tumor immunogenicity and PD-L1 silencing for synergistic antitumor immunotherapy.

BACKGROUND: PD-1/PD-L1 blockade has become a powerful method to treat malignant tumors. However, a large proportion of patients still do not benefit from this treatment, due to low tumor immunogenicity and low tumor penetration of the agents. Recently, neutrophil elastase has been shown to induce robust tumor immunogenicity, while the insufficient enzyme activity at the tumor site restricted its anti-tumor application. Here, we designed polyethyleneimine-modified neutrophil elastase (PEI-elastase) loaded with PD-L1small interfering RNA (PD-L1 siRNA) for improving enzymatic activity and delivering siRNA to tumor, which was expected to solve the above-mentioned problems. RESULTS: We first demonstrated that PEI-elastase possessed high enzymatic activity, which was also identified as an excellent gene-delivery material. Then, we synthesized anti-tumor lipopolymer (P-E/S Lip) by encapsulating PEI-elastase and PD-L1siRNA with pH-responsive anionic liposomes. The P-E/S Lip could be rapidly cleaved in tumor acidic environment, leading to exposure of the PEI-elastase/PD-L1 siRNA. Consequently, PEI-elastase induced powerful tumor immunogenicity upon direct tumor killing with minimal toxicity to normal cells. In parallel, PEI-elastase delivered PD-L1siRNA into the tumor and reduced PD-L1 expression. Orthotopic tumor administration of P-E/S Lip not only attenuated primary tumor growth, but also produced systemic anti-tumor immune response to inhibit growth of distant tumors and metastasis. Moreover, intravenous administration of P-E/S Lip into mice bearing subcutaneous tumors leaded to an effective inhibition of established B16-F10 tumor and 4T1 tumor, with histological analyses indicating an absence of detectable toxicity. CONCLUSIONS: In our study, a protease-based nanoplatform was used to cooperatively provoke robust tumor immunogenicity and down-regulate PD-L1 expression, which exhibited great potential as a combination therapy for precisely treating solid tumors.

The IL-1 family in tumorigenesis and antitumor immunity.

The IL-1 family of cytokines consists of IL-1α, IL-1ß, IL-18, IL-33, IL-36α, IL-36ß, and IL-36γ. These proteins form four signaling receptor complexes: the IL-1 receptor (IL-1R1 and IL-1RAcP), the IL-18 receptor (IL-18Rα and IL-18Rß), the IL-33 receptor (ST2 and IL-1RAcP), and the IL-36 receptor (IL-1Rrp2 and IL-1RAcP). The formation of receptor complexes is also regulated by various antagonistic molecules and decoy receptors. The IL-1 family cytokines are induced and secreted by both innate immune cells and tissue cells upon infection and tissue damage. Thus, they play a diverse role in mediating both innate and adaptive immune responses. During tumor development and cancer treatment, the expression of the IL-1 gene family is differentially regulated in tumor cells, tissue stromal cells, and immune cells in a stage specific and tissue specific manner. Like other cytokines, the IL-1 family proteins have pleiotropic functions that are dependent on diverse arrays of target cells. As a result, they play a complex role in tumorigenesis, cancer metastasis, immune suppression, and cancer immune surveillance. Here, we focus on reviewing experimental evidence demonstrating how members of the IL-1 family influence cancer development at the cellular and molecular level. The unique mechanisms of this group of cytokines make them attractive targets for new cancer therapy.

Immunotherapy as a New Therapeutic Approach for Brain and Spinal Cord Tumors.

Historically, the central nervous system (CNS) was considered an immune-privileged organ. However, recent studies have shown that the immune system plays a significant role in the CNS. Thus, there is renewed interest in applying cancer immunotherapy to CNS malignancies with the hope of generating a robust anti-tumor immune response and creating long-lasting immunity in patients. There has been some work with non-specific immunotherapy such as IL-2 for brain metastasis. Unfortunately, the results from non-specific immunotherapy studies were lackluster, so the focus has shifted to more specific CNS immunotherapies including cancer vaccines, immune checkpoint inhibitors, oncolytic virus therapy, and chimeric antigen receptor (CAR) T cell therapy. With respect to cancer vaccines, rindopepimut has been well-studied in glioblastoma (GBM) patients with the EGFRvIII mutation, with early results from phase II trials showing possible efficacy in carefully selected GBM patients. Other antigen-specific CNS tumor vaccines are still in the early stages. Immune checkpoint inhibitors are amongst the most promising and widely studied CNS immunotherapy strategies. Anti-PD-1 showed promising results in many non-CNS solid tumors, however, results from early clinical trials show poor efficacy for anti-PD-1 in GBM patients. Anti-PD-1 is also under investigation for CNS metastasis and showed some efficacy in non-small cell lung cancer and renal cell carcinoma patients. Anti-PD-1 is under early stage investigation for other CNS tumors such as chordoma. Oncolytic virus therapy is the strategy of infecting tumor cells with a virus that in turn triggers an innate immune response leading to tumor cell lysis. Oncolytic viruses currently under investigation include several adenovirus-based therapies and a herpes simplex virus-based therapy. Phase I studies have demonstrated the safety of oncolytic virus therapies in GBM patients. Current studies are evaluating the efficacy of these therapies both alone and in combination with other immunotherapy approaches such as checkpoint inhibition in patients with CNS tumors. CAR T cell therapy is a newer immunotherapy approach. CAR T cell therapies, directed against EGFRvIII mutation and HER-2 mutation, demonstrate an acceptable safety profile, although there is no conclusive evidence of the survival benefit of these therapies in early trials. Studies are currently underway to determine optimal tumor-specific antigen selection and modality of administration for CAR T cell therapy. Overall, the prognosis is generally poor for patients with CNS malignancies. The promising results of cancer immunotherapy for non-CNS tumors have created significant interest in applying these therapies for CNS malignancies. Preliminary results have not demonstrated robust efficacy for CNS immunotherapy. However, it is important to keep in mind that the field is still in its infancy and many clinical trials are still early-phase. Several, clinical trials are currently underway to further explore the role of immunotherapy for CNS malignancies.

Steatohepatitis Impairs T-cell-Directed Immunotherapies Against Liver Tumors in Mice.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis causes loss of hepatic CD4+ T cells and promotes tumor growth. The liver is the most common site of distant metastases from a variety of malignancies, many of which respond to immunotherapy. We investigated the effects of steatohepatitis on the efficacy of immunotherapeutic agents against liver tumors in mice. METHODS: Steatohepatitis was induced by feeding C57BL/6NCrl or BALB/c AnNCr mice a methionine and choline-deficient diet or a choline-deficient l-amino acid-defined diet. Mice were given intrahepatic or subcutaneous injections of B16 melanoma and CT26 colon cancer cells, followed by intravenous injections of M30-RNA vaccine (M30) or intraperitoneal injections of an antibody against OX40 (aOX40) on days 3, 7, and 10 after injection of the tumor cells. We measured tumor growth and analyzed immune cells in tumor tissues by flow cytometry. Mice were given N-acetylcysteine to prevent loss of CD4+ T cells from liver. RESULTS: Administration of M30 and aOX40 inhibited growth of tumors from intrahepatic injections of B16 or CT26 cells in mice on regular diet. However, M30 and/or aOX40 did not slow growth of liver tumors from B16 or CT26 cells in mice with diet-induced steatohepatitis (methionine and choline-deficient diet or choline-deficient l-amino acid-defined diet). Steatohepatitis did not affect the ability of M30 to slow growth of subcutaneous B16 tumors. In mice with steatohepatitis given N-acetylcysteine, which prevents loss of CD4+ T cells, M30 and aOX40 were able slow growth of hepatic tumors. Flow cytometry analysis of liver tumors revealed reduced CD4+ T cells and effector memory cells in mice with vs without steatohepatitis. CONCLUSIONS: Steatohepatitis reduces the abilities of immunotherapeutic agents, such as M30 and aOX40, to inhibit tumor liver growth by reducing tumor infiltration by CD4+ T cells and effector memory cells. N-acetylcysteine restores T-cell numbers in tumors and increases the ability of M30 and aOX40 to slow tumor growth in mice.

TET2 promotes anti-tumor immunity by governing G-MDSCs and CD8+ T-cell numbers.

The host immune response is a fundamental mechanism for attenuating cancer progression. Here we report a role for the DNA demethylase and tumor suppressor TET2 in host anti-tumor immunity. Deletion of Tet2 in mice elevates IL-6 levels upon tumor challenge. Elevated IL-6 stimulates immunosuppressive granulocytic myeloid-derived suppressor cells (G-MDSCs), which in turn reduce CD8+ T cells upon tumor challenge. Consequently, systematic knockout of Tet2 in mice leads to accelerated syngeneic tumor growth, which is constrained by anti-PD-1 blockade. Removal of G-MDSCs by the anti-mouse Ly6g antibodies restores CD8+ T-cell numbers in Tet2-/- mice and reboots their anti-tumor activity. Importantly, anti-IL-6 antibody treatment blocks the expansion of G-MDSCs and inhibits syngeneic tumor growth. Collectively, these findings reveal a TET2-mediated IL-6/G-MDSCs/CD8+ T-cell immune response cascade that safeguards host adaptive anti-tumor immunity, offering a cell non-autonomous mechanism of TET2 for tumor suppression.

Protein 4.1R affects photodynamic therapy for B16 melanoma by regulating the transport of 5-aminolevulinic acid.

Melanoma is the most aggressive malignant tumor of skin cancer as it can grow rapidly and metastasize. Photodynamic therapy (PDT) is a promising cancer ablation method for skin tumors, although it lacks efficiency owing to factors such as tumor characteristics, delivery of photosensitizers, immune response in vivo etc. Extensive investigation of molecules that can potentially modulate treatment efficacy is required. Protein 4.1R is a cytoskeletal protein molecule. Previous studies have shown that protein 4.1R knockdown reduces PDT sensitivity in mouse embryonic fibroblast cells. However, the functional role of protein 4.1R in melanoma is unclear. In this study, we aimed to elucidate the effect of protein 4.1R on PDT for melanoma in mice and the mechanism of anti-tumor immunity. Our results indicated that CRISPR/Cas9-mediated protein 4.1R knockout promotes the proliferation, migration, and invasion of B16 cells. We further investigated the potential mechanism of protein 4.1R on tumor cell PDT sensitivity. Our results showed that protein 4.1R knockout reduced the expression of membrane transporters γ-aminobutyric acid transporter (GAT)-1 and (GAT)-2 in B16 cells, which affected 5-ALA transmembrane transport and reduced the efficiency of PDT on B16 cells. Protein 4.1R knockout downregulated the anti-tumor immune response triggered by PDT in vivo. In conclusion, our data suggest that protein 4.1R is an important regulator in PDT for tumors and may promote the progress and efficacy of melanoma treatment.

Therapeutic Perspectives of CD26 Inhibitors in Imune-Mediated Diseases.

The enzymatic activity of CD26/DPP4 (dipeptidyl peptidase 4/DPP4) is highlighted in multiple studies to play a vital role in glucose metabolism by cleaving and inactivating the incretins glucagon-like peptide-1 (GLP) and gastric inhibitory protein (GIP). A large number of studies demonstrate that CD26 also plays an integral role in the immune system, particularly in T cell activation. CD26 is extensively expressed in immune cells, such as T cells, B cells, NK cells, dendritic cells, and macrophages. The enzymatic activity of CD26 cleaves and regulates numerous chomokines and cytokines. CD26 inhibitors have been widely used for the treatment of diabetes mellitus, while it is still under investigation as a therapy for immune-mediated diseases. In addition, CD26's involvement in cancer immunology was also described. The review aims to summarize the therapeutic effects of CD26 inhibitors on immune-mediated diseases, as well as the mechanisms that underpin them.

Toll-Like Receptors (TLRs) in the Tumor Microenvironment (TME): A Dragon-Like Weapon in a Non-fantasy Game of Thrones.

Toll-like receptors (TLRs) in the tumor microenvironment (TME) are expressed not only in innate and adaptive immune cells but also in stromal cells such as fibroblasts, endothelial cells (EC), and tumor cells. The role of TLR signaling in the TME is complex and controversial due to their wide expression within the TME. Moreover, TLR signaling may culminate in different outcomes depending on the type of tumor, the implicated TLR, the type of TLR ligands, and, most importantly, the main type of cell(s) that are targeted by TLR ligands. Understanding to what extent these complex TLR signals impact on tumor progression merits further investigation, as it can help improve existing anti-cancer treatments or unravel new ones. In most cases, TLR signaling in tumor cells and in immune cells is associated with pro-tumoral and anti-tumoral effects, respectively. A better understanding of the relationship between TLRs and the TME, especially in humans, is required to design better anti-cancer therapies, considering that most current TLR-involved treatments were disappointing in clinical trials.In this chapter, we will discuss the impact of TLR signaling on the hallmarks of cancer, by highlighting their effects in tumor, immune, and stromal cells within the TME. Furthermore, we will discuss how the understanding of the role of TLRs can pave the way to develop new anti-cancer treatments and even predict clinical outcome and chemotherapy efficacy.

Perspectives in Manipulating EVs for Therapeutic Applications: Focus on Cancer Treatment.

Extracellular vesicles (EVs) receive special attention from oncologists due to their assumed usefulness as prognostic markers, vaccines to induce anti-cancer immune response, and physiological delivery tools. The latter application, which supports the reduction of side effects of treatment, is still fraught with many challenges, including established methods for loading EVs with selected cargo and directing them towards target cells. EVs could be loaded with selected cargo either in vitro using several physicochemical techniques, or in vivo by modification of parental cell, which may have an advantage over in vitro procedures, since some of them significantly influence EVs' properties. Otherwise, our research findings suggest that EVs could be passively supplemented with micro RNAs (miRNAs) or miRNA antagonists to induce expected biological effect. Furthermore, our observations imply that antigen-specific antibody light chains could coat the surface of EVs to increase the specificity of cell targeting. Finally, the route of EVs' administration also determines their bioavailability and eventually induced therapeutic effect. Besides, EV membrane lipids may possibly possess immune adjuvant activity. The review summarizes the current knowledge on the possibilities to manipulate EVs to use them as a delivery tool, with the special emphasis on anti-cancer therapy.

FOXOs in cancer immunity: Knowns and unknowns.

In the tumor microenvironment (TME), cancer cells, stromal cells, and immune cells, along with their extracellular factors, have profound effects on either promoting or repressing anti-cancer immunity. Accumulating evidence has shown the paradoxical intrinsic role of the Forkhead box O (FOXO) family of transcription factors in cancer, which can act as a tumor repressor while also maintaining cancer stem cells. FOXOs also regulate cancer immunity. FOXOs promote antitumor activity through negatively regulating the expression of immunosuppressive proteins, such as programmed death 1 ligand 1 (PD-L1), and vascular endothelial growth factor (VEGF) in tumor cells or stromal cells, which can shape an immunotolerant state in the TME. FOXOs also intrinsically control the anti-tumor immune response as well as the homeostasis and development of immune cells, including T cells, B cells, natural killer (NK) cells, macrophages, and dendritic cells. As a cancer repressor, reviving the activity of Foxo1 forces tumor-infiltrating activated regulatory T (Treg) cells to egress from tumor tissues. As a promoter of cancer development, Foxo3 and Foxo1 negatively regulate cytotoxicity of both CD8+ T cells and NK cells against tumor cells. In this review, we focus on the complex role of FOXOs in regulating cancer immunity due to the various roles that they play in cancer cells, stromal cells, and immune cells. We also speculate on some possible additional roles of FOXOs in cancer immunity based on findings regarding FOXOs in non-cancer settings, such as infectious disease.

Interleukin 35 Expression Correlates With Microvessel Density in Pancreatic Ductal Adenocarcinoma, Recruits Monocytes, and Promotes Growth and Angiogenesis of Xenograft Tumors in Mice.

BACKGROUND & AIMS: Cells of the monocyte lineage contribute to tumor angiogenesis. Interleukin 35 (IL35) is a member of the IL12 family produced by regulatory, but not effector, T cells. IL35 is a dimer comprising the IL12 alpha and IL27 beta chains, encoded by IL12A and EBI3, respectively. Expression of IL35 is increased in pancreatic ductal adenocarcinomas (PDACs) compared with normal pancreatic tissues, and promotes metastasis. We investigated the role of IL35 in monocyte-induced angiogenesis of PDAC in mice. METHODS: We measured levels of IL35 protein, microvessel density, and numbers of monocytes in 123 sequential PDAC tissues from patients who underwent surgery in China in 2010. We performed studies with the human PDAC cell lines CFPAC-1, BxPC-3, Panc-1, MIA-PaCa-2, and mouse PDAC cell line Pan02. Monocyte subsets were isolated by flow cytometry from human peripheral blood mononuclear cells. Fused human or mouse IL12A and EBI3 genes were overexpressed in PDAC cells or knocked down using small hairpin RNAs. Cells were grown as xenograft tumors in SCID mice; some mice were given injections of an IL35-neutralizing antibody and tumor growth was monitored. We performed chemotaxis assays to measure the ability of IL35 to recruit monocytes. We analyzed mRNA sequences of 179 PDACs in the Cancer Genome Atlas to identify correlations between expression of IL12A and EBI3 and monocyte markers. Monocytes incubated with IL35 or PDAC cell supernatants were analyzed in tube formation and endothelial migration assays. RESULTS: In PDAC samples from patients, levels of IL35 mRNA and protein correlated with microvessel density and infiltration of monocyte lineage cells. In cells and mice with xenograft tumors, IL35 increased recruitment of monocytes into PDAC tumors, which required CCL5. Upon exposure to IL35, monocytes increased expression of genes whose products promote angiogenesis (CXCL1 and CXCL8). IL35 activated transcription of CCL5, CXCL1, and CXCL8 by inducing GP130 signaling, via IL12RB2 and phosphorylation of STAT1 and STAT4. A combination of a neutralizing antibody against IL35 and gemcitabine significantly decreased monocyte infiltration, microvessel density, and volume of xenograft tumors grown from PDAC cells in mice. CONCLUSIONS: PDAC cells produce IL35 to recruit monocytes via CCL5 and induce macrophage to promote angiogenesis via expression of CXCL1 and CXCL8. IL35 signaling promotes angiogenesis and growth of xenograft tumors from PDAC cells in mice. IL35 might serve as a therapeutic target for patients with pancreatic cancer.

A Chimeric Antibody against ACKR3/CXCR7 in Combination with TMZ Activates Immune Responses and Extends Survival in Mouse GBM Models.

Glioblastoma (GBM) is the least treatable type of brain tumor, afflicting over 15,000 people per year in the United States. Patients have a median survival of 16 months, and over 95% die within 5 years. The chemokine receptor ACKR3 is selectively expressed on both GBM cells and tumor-associated blood vessels. High tumor expression of ACKR3 correlates with poor prognosis and potential treatment resistance, making it an attractive therapeutic target. We engineered a single chain FV-human FC-immunoglobulin G1 (IgG1) antibody, X7Ab, to target ACKR3 in human and mouse GBM cells. We used hydrodynamic gene transfer to overexpress the antibody, with efficacy in vivo. X7Ab kills GBM tumor cells and ACKR3-expressing vascular endothelial cells by engaging the cytotoxic activity of natural killer (NK) cells and complement and the phagocytic activity of macrophages. Combining X7Ab with TMZ allows the TMZ dosage to be lowered, without compromising therapeutic efficacy. Mice treated with X7Ab and in combination with TMZ showed significant tumor reduction by MRI and longer survival overall. Brain-tumor-infiltrating leukocyte analysis revealed that X7Ab enhances the activation of M1 macrophages to support anti-tumor immune response in vivo. Targeting ACKR3 with immunotherapeutic monoclonal antibodies (mAbs) in combination with standard of care therapies may prove effective in treating GBM.

Optimizing cancer immunotherapy: Is it time for personalized predictive biomarkers?

Cancer immunotherapy, a treatment that selectively augments a patient's anti-tumor immune response, is a breakthrough advancement in personalized medicine. A subset of cancer patients undergoing immunotherapy have displayed robust and long-lasting therapeutic responses. Currently, the spotlight is on the use of blocking antibodies against the T-cell checkpoint molecules, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programed cell death-1 (PD-1)/programed death-ligand 1 (PD-L1), which have been effectively used to combat many cancers types. Despite the overall enthusiasm, immune checkpoint blockade inhibitors suffer from significant limitations such as high cost, serious toxicity in a substantial proportion of patients, and a response rate as low as 10%-40% in some clinical trials. Consequently, there is an urgent and unmet medical need for companion biomarkers that could both predict the response of individual patients to these therapies, and provide the means for precise monitoring of their therapeutic outcome. In this era of precision medicine, predictive biomarkers are a hot commodity because they can effectively separate responders from non-responders, and spare non-responders from serious therapy-related toxicity. Emerging predictive biomarkers for immune checkpoint blockade are: PD-L1 expression, increased amounts of tumor-infiltrating lymphocytes, increased mutational load and mismatch repair deficiency. Other well-studied biomarkers include inflammatory infiltrate, absolute lymphocyte count and lactate dehydrogenase levels. We review recent progress on predictive cancer biomarkers in immunotherapy, with a special emphasis on serum autoantibodies that have the potential to be personalized for optimal clinical outcomes.

The impact of γ-irradiation on the induction of bystander killing by genetically engineered ovarian tumor cells: implications for clinical use.

BACKGROUND: Cellular based therapeutic approaches for cancer rely on careful consideration of finding the optimal cell to execute the cellular goal of cancer treatment. Cell lines and primary cell cultures have been used in some studies to compare the in vitro and in vivo efficacy of autologous vs allogeneic tumour cell vaccines. METHODS: This study examines the effect of γ-irradiation on a range of tumor cell lines in conjunction with suicide gene therapy of cancer. To determine the efficacy of this modality, a series of in vitro and in vivo experiments were conducted using genetically modified and unmodified tumor cell lines. RESULTS: Following co-culture of HSV-TK modified tumor cells and unmodified tumor cells both in vitro and in vivo we observed that the PA-STK ovarian tumor cells were sensitive to γ-irradiation, completely abolishing their ability to induce bystander killing of unmodified tumor cells. In contrast, TK-modified human and mouse mesothelioma cells were found to retain their in vitro and in vivo bystander killing effect after γ-irradiation. Morphological evidence was consistent with the death of PA-STK cells being by pyknosis after γ-irradiation. These results suggest that PA-STK cells are not suitable for clinical application of suicide gene therapy of cancer, as lethal γ-irradiation (100 Gy) interferes with their bystander killing activity. However, the human mesothelioma cell line CRL-5830-TK retained its bystander killing potential after exposure to similarly lethal γ-irradiation (100 Gy). CRL-5830 may therefore be a suitable vehicle for HSV-TK suicide gene therapy. CONCLUSIONS: This study highlights the diversity among tumor cell lines and the careful considerations needed to find the optimal tumor cell line for this type of suicide gene therapy of cancer.

2'-5' Oligoadenylate synthetase-like 1 (OASL1) deficiency in mice promotes an effective anti-tumor immune response by enhancing the production of type I interferons.

Type I interferon (IFN-I) plays a critical role in antiviral and antitumor defense. In our previous studies, we showed that IFN-I-inducible 2'-5' oligoadenylate synthetase-like 1 (OASL1) negatively regulates IFN-I production upon viral infection by specifically inhibiting translation of the IFN-I-regulating master transcription factor, interferon regulatory factor 7 (IRF7). In this study, we investigated whether OASL1 plays a negative role in the anti-tumor immune response by using OASL1-deficient (Oasl1 (-/-)) mice and transplantable syngeneic tumor cell models. We found that Oasl1 (-/-) mice demonstrate enhanced resistance to lung metastatic tumors and subcutaneously implanted tumors compared to wild-type (WT) mice. Additionally, we found that cytotoxic effector cells such as CD8(+) T cells (including tumor antigen-specific CD8(+) T cells) and NK cells as well as CD8α(+) DCs (the major antigen cross-presenting cells) were much more frequent (>fivefold) in the Oasl1 (-/-) mouse tumors. Furthermore, the cytotoxic effector cells in Oasl1 (-/-) mouse tumors seemed to be more functionally active. However, the proportion of immunosuppressive myeloid-derived suppressor cells within hematopoietic cells and of regulatory T cells within CD4(+) T cells in Oasl1 (-/-) mouse tumors did not differ significantly from that of WT mice. Tumor-challenged Oasl1 (-/-) mice expressed increased levels of IFN-I and IRF7 protein in the growing tumor, indicating that the enhanced antitumor immune response observed in Oasl1 (-/-) mice was caused by higher IFN-I production in Oasl1 (-/-) mice. Collectively, these results show that OASL1 deficiency promotes the antitumor immune response, and thus, OASL1 could be a good therapeutic target for treating tumors.

Requirement of interleukin 7 signaling for anti-tumor immune response under lymphopenic conditions in a murine lung carcinoma model.

Induction of lymphopenia before adoptive transfer of T cells was followed by lymphopenia-induced proliferation (LIP) and generated a potent anti-tumor immune response in rodents and in a clinical setting. Previously, we reported that CD28 signaling is essential for the differentiation of functional effector cytotoxic T lymphocytes (CTLs) under lymphopenic conditions and sequential LIP of T cells. In this study, to clarify the correlation between LIP and the anti-tumor effect, LIP was inhibited with interleukin 7 (IL7) receptor blockade at various stages, and the anti-tumor effect then assessed. We confirmed that IL7 signaling at the start of LIP is crucial for the anti-tumor immune response. In contrast, continuous IL7 signaling was not required for tumor regression, although LIP of naïve CD8+ T cells is usually regulated by IL7. The expansion and migration of CTLs in lymphopenic hosts depend on IL7 signaling during the induction phase. Here, we propose that IL7 signaling and subsequent LIP of T cells have distinct roles in the induction of T cell immunity during lymphopenia.

Poly (I:C) enhances the anti-tumor activity of canine parvovirus NS1 protein by inducing a potent anti-tumor immune response.

The canine parvovirus NS1 (CPV2.NS1) protein selectively induces apoptosis in the malignant cells. However, for an effective in vivo tumor treatment strategy, an oncolytic agent also needs to induce a potent anti-tumor immune response. In the present study, we used poly (I:C), a TLR3 ligand, as an adjuvant along with CPV2.NS1 to find out if the combination can enhance the oncolytic activity by inducing a potent anti-tumor immune response. The 4T1 mammary carcinoma cells were used to induce mammary tumor in Balb/c mice. The results suggested that poly (I:C), when given along with CPV2.NS1, not only significantly reduced the tumor growth but also augmented the immune response against tumor antigen(s) as indicated by the increase in blood CD4+ and CD8+ counts and infiltration of immune cells in the tumor tissue. Further, blood serum analysis of the cytokines revealed that Th1 cytokines (IFN-γ and IL-2) were significantly upregulated in the treatment group indicating activation of cell-mediated immune response. The present study reports the efficacy of CPV2.NS1 along with poly (I:C) not only in inhibiting the mammary tumor growth but also in generating an active anti-tumor immune response without any visible toxicity. The results of our study may help in developing CPV2.NS1 and poly (I: C) combination as a cancer therapeutic regime to treat various malignancies.

Potential role of p53 deregulation in modulating immune responses in human malignancies: A paradigm to develop immunotherapy.

The crucial role played by the oncogenic expression of TP53, stemming from mutation or amyloid formation, in various human malignancies has been extensively studied over the past two decades. Interestingly, the potential role of TP53 as a crucial player in modulating immune responses has provided new insight into the field of cancer biology. The loss of p53's transcriptional functions and/or the acquisition of tumorigenic properties can efficiently modulate the recruitment and functions of myeloid and lymphoid cells, ultimately leading to the evasion of immune responses in human tumors. Consequently, the oncogenic nature of the tumor suppressor p53 can dynamically alter the function of immune cells, providing support for tumor progression and metastasis. This review comprehensively explores the dual role of p53 as both the guardian of the genome and an oncogenic driver, especially in the context of regulation of autophagy, apoptosis, the tumor microenvironment, immune cells, innate immunity, and adaptive immune responses. Additionally, the focus of this review centers on how p53 status in the immune response can be harnessed for the development of tailored therapeutic strategies and their potential application in immunotherapy against human malignancies.

A facile boronophenylalanine modified polydopamine dual drug-loaded nanoparticles for enhanced anti-tumor immune response in hepatocellular carcinoma comprehensive treatment.

Hepatocellular carcinoma (HCC) has an insidious onset and high malignancy. Most patients have progressed to intermediate and advanced stages by the time of diagnosis, and the long-term efficacy of traditional treatments is not satisfactory. Immunotherapy has shown great promise in the treatment of HCC in recent years; however, the low immunogenicity and severe immunosuppressive tumor microenvironment result in a low response rate to immunotherapy in HCC patients. Therefore, it is of great significance to improve the immunogenicity of HCC and thus enhance its sensitivity to immunotherapy. Here, we prepared the boronophenylalanine-modified dual drug-loaded polydopamine nanoparticles by a facile method. This system used boronophenylalanine-modified polydopamine nanoparticles as a delivery vehicle and photothermal material for the chemotherapeutic drug doxorubicin and the immune agonist CpG oligodeoxynucleotides (CpG-ODN), with both active targeting and lysosomal escape functions. The cancer cells are rapidly killed by photothermal treatment, and then chemotherapy is used to further kill cancer cells that are inadequately treated by photothermal treatment. The combination of photothermal-chemotherapy synergistically induces the release of relevant antigens from tumor cells, thus initiating anti-tumor immunity; and then cooperates with CpG-ODN to trigger a powerful anti-tumor immune memory effect, potently and durably inhibiting HCC recurrence.