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Drug resistance is a significant challenge in cancer chemotherapy and is a primary factor contributing to poor recovery for cancer patients. Although drug-loaded nanoparticles have shown promise in overcoming chemotherapy resistance, they often carry a combination of drugs and require advanced design and manufacturing processes. Furthermore, they seldom approach chemotherapy-resistant tumors from an immunotherapy perspective. In this study, we developed a therapeutic nanovaccine composed solely of chemotherapy-induced resistant tumor antigens (CIRTAs) and the immune adjuvant Toll-like receptor (TLR) 7/8 agonist R848 (CIRTAs@R848). This nanovaccine does not require additional carriers and has a simple production process. It efficiently delivers antigens and immune stimulants to dendritic cells (DCs) simultaneously, promoting DCs maturation. CIRTAs@R848 demonstrated significant tumor suppression, particularly when used in combination with the immune checkpoint blockade (ICB) anti-PD-1 (αPD-1). The combined therapy increased the infiltration of T cells into the tumor while decreasing the proportion of regulatory T cells (Tregs) and modulating the tumor microenvironment, resulting in long-term immune memory. Overall, this study introduces an innovative strategy for treating chemotherapy-resistant tumors from a novel perspective, with potential applications in personalized immunotherapy and precision medicine.
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Vacunas contra el Cáncer , Desoxicitidina , Resistencia a Antineoplásicos , Gemcitabina , Inmunoterapia , Nanopartículas , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Desoxicitidina/farmacología , Animales , Inmunoterapia/métodos , Resistencia a Antineoplásicos/efectos de los fármacos , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Nanopartículas/química , Ratones , Humanos , Células Dendríticas/inmunología , Células Dendríticas/efectos de los fármacos , Línea Celular Tumoral , Ratones Endogámicos C57BL , Femenino , Imidazoles/farmacología , Imidazoles/uso terapéutico , Microambiente Tumoral/efectos de los fármacos , Antígenos de Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , NanovacunasRESUMEN
Due to the insufficient Cu+ accumulation, Cu+ efflux mechanism, and highly immunosuppressive tumor microenvironment (TME) in lung metastasis, the cuproptosis efficacy is limited. Herein, an inhalable nanodevice (CLDCu) is constructed to successfully overcome the drawbacks of cuproptosis. CLDCu consists of a Cu2+-chitosan shell and low molecular weight heparin-tocopherol succinate (LMWH-TOS, LT) core with disulfiram (DSF) loading. The prepared CLDCu can be inhaled and accumulate in large amounts in lung lesions (63.6%) with 56.5 times higher than intravenous injection. Within tumor cells, the mild acidity triggers the co-release of DSF and Cu2+, thus generating bis(diethyldithiocarbamate)-copper (CuET) to block Cu+ efflux protein ATP7B and forming toxic Cu+, leading to enhanced cuproptosis. Meanwhile, the released chitosan cooperates with CLDCu-induced cuproptosis to activate stimulator of interferon genes (STING) pathway, which significantly potentiates dendritic cells (DCs) maturation, as wells as evokes innate and adaptive immunity. In lung metastatic mice model, CLDCu is found to induce cuproptosis and reverse the immunosuppressive TME by inhalation administration. Moreover, CLDCu combined with anti-programmed cell death protein ligand-1 antibody (aPD-L1) provokes stronger antitumor immunity. Therefore, nanomedicine that combines cuproptosis with STING activation is a novel strategy for tumor immunotherapy.
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Electronic cigarettes (e-cigarettes) are thought to pose low risk of cancer because the components of e-cigarette liquid are not carcinogens. We analyzed the effects of the two major components, PG/VG and nicotine, on tumor development in preclinical models. We found that PG/VG promoted tumor cell migration in migration assays and contributed to more aggressive, metastatic, and immunosuppressive tumors in vivo, aggravated by the presence of nicotine. Whole body exposure of mice to PG/VG and nicotine rendered animals more susceptible to developing tumors with high frequencies of infiltrating proinflammatory macrophages expressing IL-6 and TNFα. Moreover, tumor-infiltrating and circulating T cells in e-cigarette exposed mice showed increased levels of immune checkpoints including CTLA4 and PD-1. Treatment with anti-CTLA4 antibody was able to abrogate metastasis with no detrimental effects on its ability to induce tumor regression in exposed mice. These findings suggest that the major components used in e-cigarette fluid can impact tumor development through induced immunosuppression.
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Sistemas Electrónicos de Liberación de Nicotina , Nicotina , Animales , Ratones , Metástasis de la Neoplasia , Ratones Endogámicos C57BL , Línea Celular Tumoral , Antígeno CTLA-4/inmunología , Femenino , Movimiento Celular/efectos de los fármacos , Receptor de Muerte Celular Programada 1RESUMEN
BACKGROUND: The efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma (HCC) remains poor. Although serine- and arginine-rich splicing factor (SRSF) family members play crucial roles in tumors, their impact on tumor immunology remains unclear. This study aimed to elucidate the role of SRSF10 in HCC immunotherapy. METHODS: To identify the key genes associated with immunotherapy resistance, we conducted single-nuclear RNA sequencing, multiplex immunofluorescence, and The Cancer Genome Atlas and Gene Expression Omnibus database analyses. We investigated the biological functions of SRSF10 in immune evasion using in vitro co-culture systems, flow cytometry, various tumor-bearing mouse models, and patient-derived organotypic tumor spheroids. RESULTS: SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8+ T cell activity. Mechanistically, SRSF10 interacted with the 3'-untranslated region of MYB, enhancing MYB RNA stability, and subsequently upregulating key glycolysis-related enzymes including glucose transporter 1 (GLUT1), hexokinase 1 (HK1), lactate dehydrogenase A (LDHA), resulting in elevated intracellular and extracellular lactate levels. Lactate accumulation induced histone lactylation, which further upregulated SRSF10 expression. Additionally, lactate produced by tumors induced lactylation of the histone H3K18la site upon transport into macrophages, thereby activating transcription and enhancing pro-tumor macrophage activity. M2 macrophages, in turn, inhibited the enrichment of CD8+ T cells and the proportion of interferon-γ+CD8+ T cells in the tumor microenvironment (TME), thus creating an immunosuppressive TME. Clinically, SRSF10 could serve as a biomarker for assessing immunotherapy resistance in various solid tumors. Pharmacological targeting of SRSF10 with a selective inhibitor 1C8 enhanced the efficacy of programmed cell death 1 (PD-1) monoclonal antibodies (mAbs) in both murine and human preclinical models. CONCLUSIONS: The SRSF10/MYB/glycolysis/lactate axis is critical for triggering immune evasion and anti-PD-1 resistance. Inhibiting SRSF10 by 1C8 may overcome anti-PD-1 tolerance in HCC.
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Antibodies to programmed cell death protein1 (anti-PD-1) have become a promising immunotherapy for triple negative breast cancer (TNBC), blocking PD-L1 signaling from pro-tumor cells through T cell PD-1 receptor binding. Nevertheless, only 10-20% of PD-L1+ metastatic TNBC patients who meet criteria benefit from ICB, and biomarkers to predict patient response have been elusive. We have previously developed an immunological niche, consisting of a microporous implant in the subcutaneous space, that supports tissue formation whose immune composition is consistent with that within vital organs. Herein, we investigated dynamic gene expression within this immunological niche to provide biomarkers of response to anti-PD-1. In a 4T1 model of metastatic TNBC, we observed sensitivity and resistance to anti-PD-1 based on primary tumor growth and survival. The niche was biopsied before, during, and after anti-PD-1 therapy, and analyzed for cell types and gene expression indicative of treatment refractivity. Myeloid cell-to-lymphocyte ratios were altered between ICB-sensitivity and resistance. Longitudinal analysis of gene expression implicated dynamic myeloid cell function that stratified sensitivity from resistance. A niche-derived gene signature predicted sensitivity or resistance prior to therapy. Analysis of the niche to monitor immunotherapy response presents a new opportunity to personalize care and investigate mechanisms underlying treatment resistance.
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The European Larynx Organ Preservation Study (ELOS; NCT06137378) is a prospective, randomized, open-label, two-armed parallel group controlled, phase II multicenter larynx organ preservation (LOP) trial in locoregionally advanced (LA) stage III, IVA/B head and neck squamous cell carcinoma of the larynx or hypopharynx (LHSCC) amenable for total laryngectomy (TL) with PD-L1 expression within tumor tissue biopsy, calculated as CPS ≥ 1. Induction chemotherapy (IC) with docetaxel and cisplatin (TP) followed by radiation will be compared to TP plus PD-1 inhibition by pembrolizumab (MK-3475; 200 mg i.v. starting day 1 q3w for 17 cycles). After a short induction early response evaluation (ERE) 21 ± 3 days after the first cycle of IC (IC-1), responders achieving endoscopic estimated tumor surface shrinkage (ETSS) ≥30% will get an additional two cycles of IC followed by intensity-modulated radiotherapy 70-72 Gy (EQD2/α/ß = 10) aiming at LOP. Nonresponders (ETSS < 30% or progressing disease) will receive TL and bilateral neck dissection followed by postoperative radiation or chemoradiation as recommended by the clinic's multidisciplinary tumor board. Pembrolizumab treatment will be continued in the intervention arm regardless of ETSS status after IC-1 in both responders and laryngectomized nonresponders, independent of subsequent decisions on adjuvant therapy after TL. Clinical Trial Registration: clinicaltrials.gov, identifier NCT06137378.
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Gasdermin-mediated inflammatory cell death (pyroptosis) can activate protective immunity in immunologically cold tumors. Here, we performed a high-throughput screen for compounds that could activate gasdermin D (GSDMD), which is expressed widely in tumors. We identified 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB) as a direct and selective GSDMD agonist that activates GSDMD pore formation and pyroptosis without cleaving GSDMD. In mouse tumor models, pulsed and low-level pyroptosis induced by DMB suppresses tumor growth without harming GSDMD-expressing immune cells. Protection is immune-mediated and abrogated in mice lacking lymphocytes. Vaccination with DMB-treated cancer cells protects mice from secondary tumor challenge, indicating that immunogenic cell death is induced. DMB treatment synergizes with anti-PD-1. DMB treatment does not alter circulating proinflammatory cytokine or leukocyte numbers or cause weight loss. Thus, our studies reveal a strategy that relies on a low level of tumor cell pyroptosis to induce antitumor immunity and raise the possibility of exploiting pyroptosis without causing overt toxicity.
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Lymphocyte activation gene (Lag)-3 is an inhibitory co-receptor and target of immune checkpoint inhibitor (ICI) therapy for cancer. The dynamic behavior of Lag-3 was analyzed at the immune synapse upon T-cell activation to elucidate the Lag-3 inhibitory mechanism. Lag-3 formed clusters and co-localized with T-cell receptor microcluster (TCR-MC) upon T-cell activation similar to PD-1. Lag-3 blocking antibodies (Abs) inhibited the co-localization between Lag-3 and TCR-MC without inhibiting Lag-3 cluster formation. Lag-3 also inhibited MHC-II-independent stimulation and Lag-3 Ab, which did not block MHC-II binding could still block Lag-3's inhibitory function, suggesting that the Lag-3 Ab blocks the Lag-3 inhibitory signal by dissociating the co-assembly of TCR-MC and Lag-3 clusters. Consistent with the combination benefit of PD-1 and Lag-3 Abs to augment T-cell responses, bispecific Lag-3/PD-1 antagonists effectively inhibited both cluster formation and co-localization of PD-1 and Lag-3 with TCR-MC. Therefore, Lag-3 inhibits T-cell activation at TCR-MC, and the target of Lag-3 ICI is to dissociate the co-localization of Lag-3 with TCR-MC.
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Antígenos CD , Inhibidores de Puntos de Control Inmunológico , Proteína del Gen 3 de Activación de Linfocitos , Activación de Linfocitos , Receptores de Antígenos de Linfocitos T , Inhibidores de Puntos de Control Inmunológico/farmacología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Antígenos CD/inmunología , Antígenos CD/metabolismo , Humanos , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , AnimalesRESUMEN
One of the primary challenges for immune checkpoint blockade (ICB)-based therapy is the limited infiltration of T lymphocytes (T cells) into tumors, often referred to as immunologically "cold" tumors. A promising strategy to enhance the anti-tumor efficacy of ICB is to increase antigen exposure, thereby enhancing T cell activation and converting "cold" tumors into "hot" ones. Herein, we present an innovative all-in-one therapeutic nanoplatform to realize local mild photothermal- and photodynamic-triggered antigen exposure, thereby improving the anti-tumor efficacy of ICB. This nanoplatform involves conjugating programmed death-ligand 1 antibody (aPD-L1) with gadolinium-doped near-infrared (NIR)-emitting carbon dots (aPD-L1@GdCDs), which displays negligible cytotoxicity in the absence of light. But under controlled NIR laser irradiation, the GdCDs produce combined photothermal and photodynamic effects. This not only results in tumor ablation but also induces immunogenic cell death (ICD), facilitating enhanced infiltration of CD8+ T cells in the tumor area. Importantly, the combination of aPD-L1 with photothermal and photodynamic therapies via aPD-L1@GdCDs significantly boosts CD8+ T cell infiltration, reduces tumor size, and improves anti-metastasis effects compared to either GdCDs-based phototherapy or aPD-L1 alone. In addition, the whole treatment process can be monitored by multi-modal fluorescence/photoacoustic/magnetic resonance imaging (FLI/PAI/MRI). Our study highlights a promising nanoplatform for cancer diagnosis and therapy, as well as paves the way to promote the efficacy of ICB therapy through mild photothermal- and photodynamic-triggered immunotherapy.
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Trichilemmal carcinoma (TC) is a rare, malignant cutaneous adnexal tumor. TC often has nonspecific clinical manifestations and its aggressive nature is frequently overlooked. Metastasis of TC is rarely reported and there is no standard treatment for recurrent or metastatic TC. We report a complicated case of TC arising from the parotid gland with metastasis to cervical lymph nodes. The tumor progressed after multiple surgeries, radiation and chemotherapy. Finally, the patient achieved good response and disease control with pembrolizumab, an immune checkpoint inhibitor targeting programmed cell death protein-1. Currently, the patient has received 19 cycles of pembrolizumab and the disease remains well controlled. This represents the first reported use of immune checkpoint blockade to treat TC.
This paper discusses a rare form of skin cancer called trichilemmal carcinoma (TC) and presents a distant metastasis TC case. The patient was treated with an immunotherapy called pembrolizumab and after 19 courses of treatment, the tumor was significantly reduced and the symptoms were relieved. This case report is the first recorded case study of pembrolizumab for the treatment of TC and provides a new approach to the treatment of challenging malignancies.
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Anticuerpos Monoclonales Humanizados , Neoplasias Cutáneas , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Masculino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Persona de Mediana Edad , Femenino , Metástasis Linfática , Metástasis de la Neoplasia , Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias de la Parótida/tratamiento farmacológico , Neoplasias de la Parótida/patologíaRESUMEN
Objectives: Aim of this study was to explore the immune-related lncRNAs having prognostic role and establishing risk score model for better prognosis and immunotherapeutic coherence for esophageal cancer (EC) patients. Methods: To determine the role of immune-related lncRNAs in EC, we analyzed the RNA-seq expression data of 162 EC patients and 11 non-cancerous individuals and their clinically relevant information from the cancer genome atlas (TCGA) database. Bioinformatic and statistical analysis such as Differential expression analysis, co-expression analysis, Kaplan Meier survival analysis, Cox proportional hazards model, ROC analysis of risk model was employed. Results: Utilizing a cutoff criterion (log2FC > 1 + log2FC < -1 and FDR < 0.01), we identified 3737 RNAs were significantly differentially expressed in EC patients. Among these, 2222 genes were classified as significantly differentially expressed mRNAs (demRNAs), and 966 were significantly differentially expressed lncRNAs (delncRNA). Through Pearson correlation analysis between differentially expressed lncRNAs and immune related-mRNAs, we identified 12 immune-related lncRNAs as prognostic signatures for EC. Notably, through Kaplan-Meier analysis on these lncRNAs, we found the low-risk group patients showed significantly improved survival compared to the high-risk group. Moreover, this prognostic signature has consistent performance across training, testing and entire validation cohort sets. Using ESTIMATE and CIBERSORT algorithm we further observed significant enriched infiltration of naive B cells, regulatory T cells resting CD4+ memory T cells, and, plasma cells in the low-risk group compared to high-risk EC patients group. On the contrary, tumor-associated M2 macrophages were highly enriched in high-risk patients. Additionally, we confirmed immune-related biological functions and pathways such as inflammatory, cytokines, chemokines response and natural killer cell-mediated cytotoxicity, toll-like receptor signaling pathways, JAK-STAT signaling pathways, chemokine signaling pathways significantly associated with identified IRlncRNA signature and their co-expressed immune genes. Furthermore, we assessed the predictive potential of the lncRNA signature in immune checkpoint inhibitors; we found that programed cell death ligand 1 (PD-L1; P-value = .048), programed cell death ligand 2 (PD-L2; P-value = .002), and T cell immunoglobulin and mucin-domain containing-3 (TIM-3; P-value = .045) expression levels were significantly higher in low-risk patients compared to high-risk patients. Conclusion: We believe this study will contribute to better prognosis prediction and targeted treatment of EC in the future.
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CD38, a multifunctional enzyme involved in NAD+ catabolism, is hypothesized to act as a metabolic checkpoint for antitumor CD8 T cells. A recent study discovered that, apart from its direct metabolic mechanisms, CD38-mediated RyR2-AKT-TCF1 signaling regulates responsiveness to anti-PD1 cancer therapy at the molecular level. These findings advocate multiprong CD38 targeting to overcome resistance to immune checkpoint blockade therapy.
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ADP-Ribosil Ciclasa 1 , Inhibidores de Puntos de Control Inmunológico , Neoplasias , Receptor de Muerte Celular Programada 1 , ADP-Ribosil Ciclasa 1/antagonistas & inhibidores , ADP-Ribosil Ciclasa 1/metabolismo , ADP-Ribosil Ciclasa 1/inmunología , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/inmunología , Transducción de Señal/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Animales , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Factor Nuclear 1-alfa del Hepatocito/genética , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Breast cancer therapy has significantly advanced by targeting the programmed cell death-ligand 1/programmed cell death-1 (PD-L1/PD-1) pathway. BMS-202 (a smallmolecule PD-L1 inhibitor) induces PD-L1 dimerization to block PD-1/PD-L1 interactions, allowing the T-cell-mediated immune response to kill tumor cells. However, immunotherapy alone has limited effects. Clinically approved photodynamic therapy (PDT) activates immunity and selectively targets malignant cells. However, PDT aggravates hypoxia, which may compromise its therapeutic efficacy and promote tumor metastasis. We designed a tumor-specific delivery nanoplatform of liposomes that encapsulate the hypoxia-sensitive antitumor drug tirapazamine (TPZ) and the small-molecule immunosuppressant BMS. New indocyanine green (IR820)-loaded polyethylenimine-folic acid (PEI-FA) was complexed with TPZ and BMS-loaded liposomes via electrostatic interactions to form lipid nanocomposites. This nanoplatform can be triggered by near-infrared irradiation to induce PDT, resulting in a hypoxic tumor environment and activation of the prodrug TPZ to achieve efficient chemotherapy. The in vitro and in vivo studies demonstrated excellent combined PDT, chemotherapy, and immunotherapy effects on the regression of distant tumors and lung metastases, providing a reference method for the preparation of targeted agents for treating breast cancer.
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Neoplasias de la Mama , Inmunoterapia , Liposomas , Liposomas/química , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/terapia , Inmunoterapia/métodos , Animales , Ratones , Humanos , Línea Celular Tumoral , Fotoquimioterapia/métodos , Verde de Indocianina/química , Verde de Indocianina/uso terapéutico , Verde de Indocianina/análogos & derivados , Ratones Endogámicos BALB C , Tirapazamina/química , Tirapazamina/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Fototerapia/métodosRESUMEN
Oral squamous cell carcinoma (OSCC) represents a prevalent head and neck malignancy with surgical intervention as the primary clinical option. Immunotherapy, particularly immune checkpoint blockade (ICB) targeting PD-1/PD-L1 shows great promise but is impeded by the immunosuppressive tumor microenvironment and low PD-L1 expression in OSCC. Herein, the "all-in-one" phototherapeutic nanoparticles (TSD NPs) are reported with balanced reactive oxygen species and photothermal conversion capacity for combined photoimmunotherapy and ICB immunotherapy against OSCC. A novel electron acceptor, 3-(dicyanomethylene)-2,3-dihydrobenzothiophene-1,1-dioxide (DTM), is introduced to develop the phototherapeutic agent with aggregation-induced emission (AIE) feature and NIR-II fluorescence centered at 1000 nm. Benefiting from the AIE feature and the DTM acceptor, the resultant TSD NPs also exhibit strong type I reactive oxygen species (ROS) generation and high photothermal conversion efficiency (45.3%), which can profoundly induce immunogenic cell death (ICD), activate cytotoxic T lymphocytes, and convert the immunosuppressive tumor microenvironment into an immune-supportive one. Additionally, TSD NPs upregulate the PD-L1 expression on OSCC cells, thus enhancing the efficacy of combined treatment with αPD-L1 ICB immunotherapy. This results show that the synergistic treatment of TSD NPs and αPD-L1 effectively eradicates solid OSCC tumors without adverse effects on normal tissues, proving a novel and promising strategy for OSCC management.
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Neoadjuvant immune checkpoint blockade (ICB) has achieved significant success in treating various cancers, leading to improved therapeutic responses and survival rates among patients. However, in colorectal cancer (CRC), ICB has yielded poor results in tumors that are mismatch repair proficient, microsatellite-stable, or have low levels of microsatellite instability (MSI-L), which account for up to 95% of CRC cases. The underlying mechanisms behind the lack of immune response in MSI-negative CRC to immune checkpoint inhibitors remain an open conundrum. Consequently, there is an urgent need to explore the intrinsic mechanisms and related biomarkers to enhance the intratumoral immune response and render the tumor "immune-reactive". Intestinal microbes, such as the oral microbiome member Fusobacterium nucleatum (F. nucleatum), have recently been thought to play a crucial role in regulating effective immunotherapeutic responses. Herein, we advocate the idea that a complex interplay involving F. nucleatum, the local immune system, and the tumor microenvironment (TME) significantly influences ICB responses. Several mechanisms have been proposed, including the regulation of immune cell proliferation, inhibition of T lymphocyte, natural killer (NK) cell function, and invariant natural killer T (iNKT) cell function, as well as modification of the TME. This review aims to summarize the latest potential roles and mechanisms of F. nucleatum in antitumor immunotherapies for CRC. Additionally, it discusses the clinical application value of F. nucleatum as a biomarker for CRC and explores novel strategies, such as nano-delivery systems, for modulating F. nucleatum to enhance the efficacy of ICB therapy.
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Unprecedented progress in immune checkpoint blockade (ICB) therapy has been made in cancer treatment. However, the response to ICB therapy is limited to a small subset of patients. The development of ICB sensitizers to improve cancer immunotherapy outcomes is urgently needed. Berberine (BBR), a well-known phytochemical compound isolated from many kinds of medicinal plants such as Berberis aristata, Coptis chinensis, and Phellondendron chinense Schneid, has shown the ability to inhibit the proliferation, invasion and metastasis of cancer cells. In this study, we investigated whether BBR can enhance the therapeutic benefit of ICB for melanoma, and explored the underlying mechanisms involved. The results showed that BBR could sensitize ICB to inhibit tumor growth and increased the survival rate of mice. Moreover, BBR stimulated intracellular ROS production partially by inhibiting NQO1 activity, which induced immunogenic cell death (ICD) in melanoma, elevated the levels of damage-associated molecular patterns (DAMPs), and subsequently activated DC cells and CD8 + T cells in vitro and in vivo. In conclusion, BBR is a novel ICD inducer. BBR could enhance the therapeutic benefit of ICB for melanoma. These effects were partially mediated through the inhibition of NQO1 and ROS activation.
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Prostate cancer (PCa) is one of the most common male genitourinary system malignancies. Despite the significant benefits of anti-PD-L1 immune checkpoint inhibitor therapy in other cancers, the reasons for its poor therapeutic efficacy in prostate cancer (PCa) remain unclear.NDR1 plays an important role in innate immunity, but its role in tumor immunity and immunotherapy has not been investigated. The role of NDR1 in the immune microenvironment of PCa and the related mechanisms are unknown. Here, we found a positive correlation between NDR1 and PD-L1 expression in PCa. NDR1 significantly inhibits CD8 + T cell infiltration and function, thereby promoting immune escape in prostate cancer.More importantly, NDR1 inhibition significantly enhanced CD8 + T cell activation, which enhanced the therapeutic effect of anti-PD-L1. Mechanistic studies revealed that NDR1 inhibits ubiquitination-mediated PD-L1 degradation via the deubiquitinase USP10, upregulates PD-L1, and promotes PCa immune escape. Thus, our study suggests a unique PD-L1 regulatory mechanism underlying PCa immunotherapy failure. The significance of NDR1 in PCa immune escape and its mechanism of action were clarified, and combined NDR1/PD-L1 inhibition was suggested as an approach to boost PCa immunotherapy effectiveness.
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Antígeno B7-H1 , Neoplasias de la Próstata , Escape del Tumor , Ubiquitina Tiolesterasa , Ubiquitinación , Masculino , Humanos , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/genética , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina Tiolesterasa/genética , Antígeno B7-H1/metabolismo , Línea Celular Tumoral , Animales , Ratones , Linfocitos T CD8-positivos/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
The combination of therapy-induced immunogenic cell death (ICD) and immune checkpoint blockade can provide a mutually reinforced strategy to reverse the poor immunogenicity and immune escape behavior of tumors. In this work, a chimeric peptide-engineered immunostimulant (ER-PPB) is fabricated for endoplasmic reticulum (ER)-targeted photodynamic immunotherapy against metastatic tumors. Among which, the amphiphilic chimeric peptide (ER-PP) is composed of ER-targeting peptide FFKDEL, hydrophilic PEG8 linker and photosensitizer protoporphyrin IX (PpIX), which could be assembled with a PD-1/PD-L1 blocker (BMS-1) to prepare ER-PPB. After passively targeting at tumor tissues, ER-PPB will selectively accumulate in the ER. Next, the localized PDT of ER-PPB will produce a lot of ROS to destroy the primary tumor cells, while increasing the ER stress to initiate a robust ICD cascade. Moreover, the concomitant delivery of BMS-1 can impede the immune escape of tumor cells through PD-1/PD-L1 blockade, thus synergistically activating the immune system to combat metastatic tumors. In vitro and in vivo results demonstrate the robust immune activation and metastatic tumor inhibition characteristics of ER-PPB, which may offer a promising strategy for spatiotemporally controlled metastatic tumor therapy.
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Aim: Immune-related (IR) colitis is a potentially life-threatening complication of checkpoint inhibitors. Its presentation often includes diarrhea, abdominal pain and rectal bleeding and the median time to onset is 6-10 weeks post initiation of immunotherapy. Case study: We report an unusual case of fulminant IR-colitis beginning 3 days after the first dose of dual checkpoint blockade. IR-colitis was refractory to high-dose corticosteroids and was further complicated by sigmoid diverticulum perforation. Conclusion: Early-onset IR-colitis can occur, particularly in the context of combined anti-PD1 and anti-CTLA4 blockade, and clinicians should maintain a high-index of suspicion even when timing of symptom onset is atypical. Further research is needed to elucidate risk factors for early-onset IR-colitis.
We report an unusual case of immune-related (IR)-colitis that occurred just 3 days after receiving treatment for liver cancer with a class of drug called immunotherapy. Immunotherapy works by enabling our own immune system to attack cancer cells that should not be present in our body. One unwanted side effect of this therapy is that our immune system can attack normal tissue and organs. IR colitis is when immunotherapy leads the immune system to attack the large intestine, and often presents with abdominal pain, diarrhea and blood in the stool. This side effect typically occurs 6-10 weeks following start of immunotherapy. This case is unusual because of the very early onset of IR colitis. The patient reported herein had a severe case of IR colitis that required the surgical team to emergently remove part of his large intestine. This case demonstrates that IR colitis can happen significantly earlier than the typical time course, highlighting the need for clinicians and patients alike to maintain a high index of suspicion for this potentially life-threatening toxicity. Future studies should aim to identify potential risk factors for early-onset IR colitis.
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Relatlimab (rela; anti-LAG-3) plus nivolumab (nivo; anti-PD-1) is safe and effective for treatment of advanced melanoma. We designed a trial (NCT03743766) where advanced melanoma patients received rela, nivo, or rela+nivo to interrogate the immunologic mechanisms of rela+nivo. Analysis of biospecimens from this ongoing trial demonstrated that rela+nivo led to enhanced capacity for CD8+ T cell receptor signaling and altered CD8+ T cell differentiation, leading to heightened cytotoxicity despite the retention of an exhaustion profile. Co-expression of cytotoxic and exhaustion signatures was driven by PRDM1, BATF, ETV7, and TOX. Effector function was upregulated in clonally expanded CD8+ T cells that emerged after rela+nivo. A rela+nivo intratumoral CD8+ T cell signature was associated with a favorable prognosis. This intratumoral rela+nivo signature was validated in peripheral blood as an elevated frequency of CD38+TIM3+CD8+ T cells. Overall, we demonstrated that cytotoxicity can be enhanced despite the retention of exhaustion signatures, which will inform future therapeutic strategies.