RESUMEN
Defective host defenses later in life are associated with changes in immune cell activities, suggesting that age-specific considerations are needed in immunotherapy approaches. In this study, we found that PD-1 and CTLA4-based cancer immunotherapies are unable to eradicate tumors in elderly mice. This defect in anti-tumor activity correlated with two known age-associated immune defects: diminished abundance of systemic naive CD8+ T cells and weak migratory activities of dendritic cells (DCs). We identified a vaccine adjuvant, referred to as a DC hyperactivator, which corrects DC migratory defects in the elderly. Vaccines containing tumor antigens and DC hyperactivators induced T helper type 1 (TH1) CD4+ T cells with cytolytic activity that drive anti-tumor immunity in elderly mice. When administered early in life, DC hyperactivators were the only adjuvant identified that elicited anti-tumor CD4+ T cells that persisted into old age. These results raise the possibility of correcting age-associated immune defects through DC manipulation.
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Linfocitos T CD4-Positivos , Células Dendríticas , Ratones Endogámicos C57BL , Células Dendríticas/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Ratones , Envejecimiento/inmunología , Linfocitos T CD8-positivos/inmunología , Inmunoterapia/métodos , Vacunas contra el Cáncer/inmunología , Femenino , Neoplasias/inmunología , Neoplasias/terapia , Receptor de Muerte Celular Programada 1/metabolismo , Antígeno CTLA-4/metabolismo , Movimiento Celular , Antígenos de Neoplasias/inmunologíaRESUMEN
Overcoming immune-mediated resistance to PD-1 blockade remains a major clinical challenge. Enhanced efficacy has been demonstrated in melanoma patients with combined nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) treatment, the first in its class to be FDA approved. However, how these two inhibitory receptors synergize to hinder anti-tumor immunity remains unknown. Here, we show that CD8+ T cells deficient in both PD-1 and LAG-3, in contrast to CD8+ T cells lacking either receptor, mediate enhanced tumor clearance and long-term survival in mouse models of melanoma. PD-1- and LAG-3-deficient CD8+ T cells were transcriptionally distinct, with broad TCR clonality and enrichment of effector-like and interferon-responsive genes, resulting in enhanced IFN-γ release indicative of functionality. LAG-3 and PD-1 combined to drive T cell exhaustion, playing a dominant role in modulating TOX expression. Mechanistically, autocrine, cell-intrinsic IFN-γ signaling was required for PD-1- and LAG-3-deficient CD8+ T cells to enhance anti-tumor immunity, providing insight into how combinatorial targeting of LAG-3 and PD-1 enhances efficacy.
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Antígenos CD , Linfocitos T CD8-positivos , Interferón gamma , Proteína del Gen 3 de Activación de Linfocitos , Ratones Endogámicos C57BL , Receptor de Muerte Celular Programada 1 , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Animales , Interferón gamma/metabolismo , Ratones , Antígenos CD/metabolismo , Comunicación Autocrina , Humanos , Melanoma/inmunología , Melanoma/tratamiento farmacológico , Femenino , Línea Celular Tumoral , Melanoma Experimental/inmunología , Agotamiento de Células TRESUMEN
The use of probiotics by cancer patients is increasing, including among those undergoing immune checkpoint inhibitor (ICI) treatment. Here, we elucidate a critical microbial-host crosstalk between probiotic-released aryl hydrocarbon receptor (AhR) agonist indole-3-aldehyde (I3A) and CD8 T cells within the tumor microenvironment that potently enhances antitumor immunity and facilitates ICI in preclinical melanoma. Our study reveals that probiotic Lactobacillus reuteri (Lr) translocates to, colonizes, and persists within melanoma, where via its released dietary tryptophan catabolite I3A, it locally promotes interferon-γ-producing CD8 T cells, thereby bolstering ICI. Moreover, Lr-secreted I3A was both necessary and sufficient to drive antitumor immunity, and loss of AhR signaling within CD8 T cells abrogated Lr's antitumor effects. Further, a tryptophan-enriched diet potentiated both Lr- and ICI-induced antitumor immunity, dependent on CD8 T cell AhR signaling. Finally, we provide evidence for a potential role of I3A in promoting ICI efficacy and survival in advanced melanoma patients.
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Limosilactobacillus reuteri , Melanoma , Microambiente Tumoral , Humanos , Dieta , Inhibidores de Puntos de Control Inmunológico , Limosilactobacillus reuteri/metabolismo , Melanoma/terapia , Triptófano/metabolismo , Linfocitos T CD8-positivos/inmunología , Receptores de Hidrocarburo de Aril/agonistasRESUMEN
Neoantigens arise from mutations in cancer cells and are important targets of T cell-mediated anti-tumor immunity. Here, we report the first open-label, phase Ib clinical trial of a personalized neoantigen-based vaccine, NEO-PV-01, in combination with PD-1 blockade in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. This analysis of 82 patients demonstrated that the regimen was safe, with no treatment-related serious adverse events observed. De novo neoantigen-specific CD4+ and CD8+ T cell responses were observed post-vaccination in all of the patients. The vaccine-induced T cells had a cytotoxic phenotype and were capable of trafficking to the tumor and mediating cell killing. In addition, epitope spread to neoantigens not included in the vaccine was detected post-vaccination. These data support the safety and immunogenicity of this regimen in patients with advanced solid tumors (Clinicaltrials.gov: NCT02897765).
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Vacunas contra el Cáncer/inmunología , Inmunoterapia/métodos , Medicina de Precisión/métodos , Anciano , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Persona de Mediana Edad , Mutación , Nivolumab/uso terapéutico , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/inmunologíaRESUMEN
Checkpoint inhibitors have revolutionized cancer treatment. However, only a minority of patients respond to these immunotherapies. Here, we report that blocking the inhibitory NKG2A receptor enhances tumor immunity by promoting both natural killer (NK) and CD8+ T cell effector functions in mice and humans. Monalizumab, a humanized anti-NKG2A antibody, enhanced NK cell activity against various tumor cells and rescued CD8+ T cell function in combination with PD-x axis blockade. Monalizumab also stimulated NK cell activity against antibody-coated target cells. Interim results of a phase II trial of monalizumab plus cetuximab in previously treated squamous cell carcinoma of the head and neck showed a 31% objective response rate. Most common adverse events were fatigue (17%), pyrexia (13%), and headache (10%). NKG2A targeting with monalizumab is thus a novel checkpoint inhibitory mechanism promoting anti-tumor immunity by enhancing the activity of both T and NK cells, which may complement first-generation immunotherapies against cancer.
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Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Escamosas , Cetuximab/uso terapéutico , Inmunidad Celular/efectos de los fármacos , Inmunoterapia , Células Asesinas Naturales/inmunología , Subfamília C de Receptores Similares a Lectina de Células NK , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Ensayos Clínicos Fase II como Asunto , Humanos , Células Asesinas Naturales/patología , Ratones , Subfamília C de Receptores Similares a Lectina de Células NK/antagonistas & inhibidores , Subfamília C de Receptores Similares a Lectina de Células NK/inmunologíaRESUMEN
In vitro cancer cultures, including three-dimensional organoids, typically contain exclusively neoplastic epithelium but require artificial reconstitution to recapitulate the tumor microenvironment (TME). The co-culture of primary tumor epithelia with endogenous, syngeneic tumor-infiltrating lymphocytes (TILs) as a cohesive unit has been particularly elusive. Here, an air-liquid interface (ALI) method propagated patient-derived organoids (PDOs) from >100 human biopsies or mouse tumors in syngeneic immunocompetent hosts as tumor epithelia with native embedded immune cells (T, B, NK, macrophages). Robust droplet-based, single-cell simultaneous determination of gene expression and immune repertoire indicated that PDO TILs accurately preserved the original tumor T cell receptor (TCR) spectrum. Crucially, human and murine PDOs successfully modeled immune checkpoint blockade (ICB) with anti-PD-1- and/or anti-PD-L1 expanding and activating tumor antigen-specific TILs and eliciting tumor cytotoxicity. Organoid-based propagation of primary tumor epithelium en bloc with endogenous immune stroma should enable immuno-oncology investigations within the TME and facilitate personalized immunotherapy testing.
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Modelos Inmunológicos , Neoplasias Experimentales/inmunología , Organoides/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Microambiente Tumoral/inmunología , Animales , Antígeno B7-H1/inmunología , Técnicas de Cocultivo , Femenino , Humanos , Inmunoterapia , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas de Neoplasias/inmunología , Neoplasias Experimentales/patología , Neoplasias Experimentales/terapia , Organoides/patologíaRESUMEN
Extensive research has elucidated the influence of the gut microbiota on human health and disease susceptibility and resistance. We review recent clinical and laboratory-based experimental studies associating the gut microbiota with certain human diseases. We also highlight ongoing translational advances that manipulate the gut microbiota to treat human diseases and discuss opportunities and challenges in translating microbiome research from and to the bedside.
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Enfermedad , Microbioma Gastrointestinal , Terapéutica , Trasplante de Microbiota Fecal , Humanos , Probióticos/uso terapéutico , Terapéutica/tendenciasRESUMEN
Cancer immunotherapies, including checkpoint inhibitors and adoptive cell therapy, manipulate the immune system to recognize and attack cancer cells. These therapies have the potential to induce durable responses in multiple solid and hematologic malignancies and thus have transformed treatment algorithms for numerous tumor types. Cancer immunotherapies lead to unique toxicity profiles distinct from the toxicities of other cancer therapies, depending on their mechanism of action. These toxicities often require specific management, which can include steroids and immune-modulating therapy and for which consensus guidelines have been published. This review will focus on the toxicities of checkpoint inhibitors and chimeric antigen receptor T cells, including pathophysiology, diagnosis, and management.
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Factores Inmunológicos/uso terapéutico , Inmunoterapia/métodos , Neoplasias/terapia , HumanosRESUMEN
Uncoupling toxicity from therapeutic effect lies at the foundation of the current state of the field of cutaneous immune-related adverse events to immune checkpoint inhibitor therapy. This will be achieved through understanding the drivers of toxicity, tumor response, and resistance via large, well-powered population-level studies, institutional cohort data, and cellular-level data. Increasing diagnostic specificity through the application of consensus disease definitions has the power to improve clinical care and each approach to research. Cutaneous immune-related adverse events are associated with increased survival, and their treatment must invoke the maintenance of a delicate balance between immunosuppression, anti-tumor effect of immune checkpoint inhibitor therapy, and quality of life. The multidisciplinary care of cancer patients with adverse events is critical to optimizing clinical and translational research outcomes and, as such, dermatologists are vital to moving the study of cutaneous adverse events forward.
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Exantema , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Calidad de Vida , Exantema/diagnóstico , Exantema/tratamiento farmacológico , Exantema/patología , Piel , Neoplasias/tratamiento farmacológico , Neoplasias/patologíaRESUMEN
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. However, their use is frequently associated with immune-related adverse events (irAEs) potentially affecting any organ. The mechanisms mediating such irAEs remain poorly understood and biomarkers to predict the development of irAEs are lacking. Growing evidence shows the importance of self-antigens in mediating irAEs during ICI therapy, in particular the well-described melanocyte differentiation antigens in melanoma patients. This review will focus on two novel classes of self-antigens involved in mediating autoimmune skin toxicity and pneumonitis in non-small cell lung cancer patients treated with immunotherapy. T cells specific for these self-antigens are thought to not only mediate irAEs but are thought to simultaneously mediate anti-tumor responses and are therefore associated with both autoimmune toxicity and response to ICI therapy. We further discuss emerging cellular and proteomic immune signatures of irAEs that may serve as biomarkers to help predict which patients are at higher risk of developing these irAEs. The determination of new tumor antigens involved in ICI therapy and the identification of related biomarkers brings us a step forward in the mechanistic understanding of ICIs and will help to monitor patients at higher risk of developing irAEs. Lastly, we discuss the current challenges in collecting research samples for the study of ICI-related mechanisms and in distinguishing between immune signatures of response and those of irAEs.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neoplasias , Neumonía , Enfermedades de la Piel , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Autoinmunidad , Proteómica , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias/terapia , Autoantígenos , Neumonía/diagnóstico , Neumonía/etiologíaRESUMEN
Cancer patients treated with immune checkpoint inhibitors (ICIs) are susceptible to a broad and variable array of immune-related adverse events (irAEs). With increasing clinical use of ICIs, defining the mechanism for irAE development is more critical than ever. However, it currently remains challenging to predict when these irAEs occur and which organ may be affected, and for many of the more severe irAEs, inaccessibility to the tissue site hampers mechanistic insight. This lack of understanding of irAE development in the clinical setting emphasizes the need for greater use of preclinical models that allow for improved prediction of biomarkers for ICI-initiated irAEs or that validate treatment options that inhibit irAEs without hampering the anti-tumor immune response. Here, we discuss the utility of preclinical models, ranging from exploring databases to in vivo animal models, focusing on where they are most useful and where they could be improved.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias , Animales , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias/tratamiento farmacológico , Neoplasias/etiología , Inmunoterapia/efectos adversos , BiomarcadoresRESUMEN
Immune checkpoint inhibitor therapies act through blockade of inhibitory molecules involved in the regulation of T cells, thus releasing tumor specific T cells to destroy their tumor targets. However, immune checkpoint inhibitors (ICI) can also lead to a breach in self-tolerance resulting in immune-related adverse events (irAEs) that include tissue-specific autoimmunity. This review addresses the question of whether the mechanisms that drive ICI-induced irAEs are shared or distinct with those driving spontaneous autoimmunity, focusing on ICI-induced diabetes, ICI-induced arthritis, and ICI-induced thyroiditis due to the wealth of knowledge about the development of autoimmunity in type 1 diabetes, rheumatoid arthritis, and Hashimoto's thyroiditis. It reviews current knowledge about role of genetics and autoantibodies in the development of ICI-induced irAEs and presents new studies utilizing single-cell omics approaches to identify T-cell signatures associated with ICI-induced irAEs. Collectively, these studies indicate that there are similarities and differences between ICI-induced irAEs and autoimmune disease and that studying them in parallel will provide important insight into the mechanisms critical for maintaining immune tolerance.
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Autoinmunidad , Neoplasias , Humanos , Inmunoterapia/métodos , Autoanticuerpos , Linfocitos TRESUMEN
Immunotherapy with immune checkpoint inhibitors (ICIs) is increasingly used to treat various tumor types. Determining patient responses to ICIs presents a significant clinical challenge. Although components of the tumor microenvironment (TME) are used to predict patient outcomes, comprehensive assessments of the TME are frequently overlooked. Using a top-down approach, the TME was divided into five layers-outcome, immune role, cell, cellular component, and gene. Using this structure, a neural network called TME-NET was developed to predict responses to ICIs. Model parameter weights and cell ablation studies were used to investigate the influence of TME components. The model was developed and evaluated using a pan-cancer cohort of 948 patients across four cancer types, with Area Under the Curve (AUC) and accuracy as performance metrics. Results show that TME-NET surpasses established models such as support vector machine and k-nearest neighbors in AUC and accuracy. Visualization of model parameter weights showed that at the cellular layer, Th1 cells enhance immune responses, whereas myeloid-derived suppressor cells and M2 macrophages show strong immunosuppressive effects. Cell ablation studies further confirmed the impact of these cells. At the gene layer, the transcription factors STAT4 in Th1 cells and IRF4 in M2 macrophages significantly affect TME dynamics. Additionally, the cytokine-encoding genes IFNG from Th1 cells and ARG1 from M2 macrophages are crucial for modulating immune responses within the TME. Survival data from immunotherapy cohorts confirmed the prognostic ability of these markers, with p-values <0.01. In summary, TME-NET performs well in predicting immunotherapy responses and offers interpretable insights into the immunotherapy process. It can be customized at https://immbal.shinyapps.io/TME-NET.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias , Microambiente Tumoral , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Microambiente Tumoral/inmunología , Neoplasias/inmunología , Redes Neurales de la Computación , InmunoterapiaRESUMEN
Immune checkpoint inhibitor (ICI) treatment has created the opportunity of improved outcome for patients with hepatocellular carcinoma (HCC). However, only a minority of HCC patients benefit from ICI treatment owing to poor treatment efficacy and safety concerns. There are few predictive factors that precisely stratify HCC responders to immunotherapy. In this study, we developed a tumour microenvironment risk (TMErisk) model to divide HCC patients into different immune subtypes and evaluated their prognosis. Our results indicated that virally mediated HCC patients who had more common tumour protein P53 (TP53) alterations with lower TMErisk scores were appropriate for ICI treatment. HCC patients with alcoholic hepatitis who more commonly harboured catenin beta 1 (CTNNB1) alterations with higher TMErisk scores could benefit from treatment with multi-tyrosine kinase inhibitors. The developed TMErisk model represents the first attempt to anticipate tumour tolerance of ICIs in the TME through the degree of immune infiltration in HCCs.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Microambiente Tumoral , Neoplasias Hepáticas/tratamiento farmacológico , InmunoterapiaRESUMEN
BACKGROUND: Although CDKN2A alteration has been explored as a favorable factor for tumorigenesis in pan-cancers, the association between CDKN2A point mutation (MUT) and intragenic deletion (DEL) and response to immune checkpoint inhibitors (ICIs) is still disputed. This study aims to determine the associations of CDKN2A MUT and DEL with overall survival (OS) and response to immune checkpoint inhibitors treatment (ICIs) among pan-cancers and the clinical features of CDKN2A-altered gastric cancer. METHODS: This study included 45,000 tumor patients that underwent tumor sequencing across 33 cancer types from four cohorts, the MSK-MetTropism, MSK-IMPACT, OrigiMed2020 and TCGA cohorts. Clinical outcomes and genomic factors associated with response to ICIs, including tumor mutational burden, copy number alteration, neoantigen load, microsatellite instability, tumor immune microenvironment and immune-related gene signatures, were collected in pan-cancer. Clinicopathologic features and outcomes were assessed in gastric cancer. Patients were grouped based on the presence of CDKN2A wild type (WT), CDKN2A MUT, CDKN2A DEL and CDKN2A other alteration (ALT). RESULTS: Our research showed that CDKN2A-MUT patients had shorter survival times than CDKN2A-WT patients in the MSK MetTropism and TCGA cohorts, but longer OS in the MSK-IMPACT cohort with ICIs treatment, particularly in patients having metastatic disease. Similar results were observed among pan-cancer patients with CDKN2A DEL and other ALT. Notably, CDKN2A ALT frequency was positively related to tumor-specific objective response rates to ICIs in MSK MetTropism and OrigiMed 2020. Additionally, individuals with esophageal carcinoma or stomach adenocarcinoma who had CDKN2A MUT had poorer OS than patients from the MSK-IMPACT group, but not those with adenocarcinoma. We also found reduced levels of activated NK cells, T cells CD8 and M2 macrophages in tumor tissue from CDKN2A-MUT or DEL pan-cancer patients compared to CDKN2A-WT patients in TCGA cohort. Gastric cancer scRNA-seq data also showed that CDKN2A-ALT cancer contained less CD8 T cells but more exhausted T cells than CDKN2A-WT cancer. A crucial finding of the pathway analysis was the inhibition of three immune-related pathways in the CDKN2A ALT gastric cancer patients, including the interferon alpha response, inflammatory response, and interferon gamma response. CONCLUSIONS: This study illustrates the CDKN2A MUT and DEL were associated with a poor outcome across cancers. CDKN2A ALT, on the other hand, have the potential to be used as a biomarker for choosing patients for ICI treatment, notably in esophageal carcinoma and stomach adenocarcinoma.
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Inhibidor p16 de la Quinasa Dependiente de Ciclina , Neoplasias Gástricas , Microambiente Tumoral , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/inmunología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Masculino , Femenino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Anciano , Pronóstico , Variaciones en el Número de Copia de ADN/genética , Mutación/genética , Inestabilidad de MicrosatélitesRESUMEN
Cancer vaccines have been developed as a promising way to boost cancer immunity. However, their clinical potency is often limited due to the imprecise delivery of tumor antigens. To overcome this problem, we conjugated an endogenous Toll-like receptor (TLR)2/6 ligand, UNE-C1, to human papilloma virus type 16 (HPV-16)-derived peptide antigen, E7, and found that the UNE-C1-conjugated cancer vaccine (UCV) showed significantly enhanced antitumor activity in vivo compared with the noncovalent combination of UNE-C1 and E7. The combination of UCV with PD-1 blockades further augmented its therapeutic efficacy. Specifically, the conjugation of UNE-C1 to E7 enhanced its retention in inguinal draining lymph nodes, the specific delivery to dendritic cells and E7 antigen-specific T cell responses, and antitumor efficacy in vivo compared with the noncovalent combination of the two peptides. These findings suggest the potential of UNE-C1 derived from human cysteinyl-tRNA synthetase 1 as a unique vehicle for the specific delivery of cancer antigens to antigen-presenting cells via TLR2/6 for the improvement of cancer vaccines.
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Natural killer (NK) cells eliminate infected or cancer cells via their cytotoxic capacity. NKG2A is an inhibitory receptor on NK cells and cancer cells often overexpress its ligand HLA-E to evade NK cell surveillance. Given the successes of immune checkpoint blockade in cancer therapy, NKG2A is an interesting novel target. However, anti-NKG2A antibodies have shown limited clinical response. In the pursuit of enhancing NK cell-mediated anti-tumor responses, we devised a Cas9-based strategy to delete KLRC1, encoding NKG2A, in human primary NK cells. Our approach involved electroporation of KLRC1-targeting Cas9 ribonucleoprotein resulting in effective ablation of NKG2A expression. Compared with anti-NKG2A antibody blockade, NKG2AKO NK cells exhibited enhanced activation, reduced suppressive signaling, and elevated expression of key transcription factors. NKG2AKO NK cells overcame inhibition from HLA-E, significantly boosting NK cell activity against solid and hematologic cancer cells. We validated this efficacy across multiple cell lines, a xenograft mouse model, and primary human leukemic cells. Combining NKG2A knockout with antibody coating of tumor cells further enhanced cytotoxicity through ADCC. Thus, we provide a comprehensive comparison of inhibition of the NKG2A pathway using genetic ablation and antibodies and provide novel insight in the observed differences in molecular mechanisms, which can be translated to enhance adoptive NK cell immunotherapy.
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Células Asesinas Naturales , Subfamília C de Receptores Similares a Lectina de Células NK , Ensayos Antitumor por Modelo de Xenoinjerto , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Subfamília C de Receptores Similares a Lectina de Células NK/genética , Subfamília C de Receptores Similares a Lectina de Células NK/metabolismo , Animales , Ratones , Línea Celular Tumoral , Antígenos HLA-E , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/genética , Anticuerpos Monoclonales/farmacología , Sistemas CRISPR-Cas , Eliminación de Gen , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Citotoxicidad InmunológicaRESUMEN
RATIONALE: Immune checkpoint inhibitor-related pneumonitis is a serious autoimmune event affecting up to 20% of patients with non-small cell lung cancer, yet the factors underpinning its development in some patients and not others are poorly understood. OBJECTIVES: To investigate the role of autoantibodies and autoreactive T cells against surfactant-related proteins in the development of pneumonitis. METHODS: The study cohort consisted of non-small cell lung cancer patients who gave blood samples before and during immune checkpoint inhibitor treatment. Serum was used for proteomics analyses and to detect autoantibodies present during pneumonitis. T cell stimulation assays and single-cell RNA sequencing were performed to investigate the specificity and functionality of peripheral autoreactive T cells. The findings were confirmed in a validation cohort comprising patients with non-small cell lung cancer and patients with melanoma. MEASUREMENTS AND MAIN RESULTS: Across both cohorts, patients who developed pneumonitis had higher pre-treatment levels of immunoglobulin G autoantibodies targeting surfactant protein-B. At the onset of pneumonitis, these patients also exhibited higher frequencies of CD4+ interferon-gamma-positive surfactant protein B-specific T cells, and expanding T cell clonotypes recognizing this protein, accompanied by a pro-inflammatory serum proteomic profile. CONCLUSIONS: Our data suggest that the co-occurrence of surfactant protein-B-specific immunoglobulin G autoantibodies and CD4+ T cells is associated with the development of pneumonitis during ICI therapy. Pre-treatment levels of these antibodies may represent a potential biomarker for elevated risk of developing pneumonitis and on-treatment levels may provide a diagnostic aid. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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Immune checkpoint inhibitor (ICI) therapy is effectively employed in treating various malignancies. However, the response rate is constrained to 5-30%, which is attributed to differences in immune responses across different tumors. Overcoming all obstacles of multistep immune activation with monotherapy is difficult. Here, maleimide-modified resiquimod (R848) prodrug nanoparticles (MAL-NPs) are reported and combined with radiotherapy (RT) and anti-PD1 to enhance ICI therapy. MAL-NPs can promote antigen endocytosis by dendritic cells and are radio-reduced to produce R848. When combined with RT, MAL-NPs can augment the concentration of nanoparticles at tumor sites and be selectively radio-reduced within the tumor, thereby triggering a potent antitumor immune response. The systemic immune response and long-term memory efficacy induced by MAL-NPs + RT + anti-PD1 significantly inhibit the abscopal tumor growth and prevent tumor recurrence. This strategy can achieve systemic therapy through selective training of the tumor immune microenvironment, offering a new approach to overcome the obstacles of ICI therapy.
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Nanoestructuras , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Imidazoles/farmacología , Imidazoles/uso terapéutico , Microambiente Tumoral , Línea Celular Tumoral , InmunoterapiaRESUMEN
Cancers express a large battery of genes by which they establish an immunosuppressive tumor microenvironment. Many of these genes are induced by intratumoral hypoxia through transcriptional activation mediated by hypoxia-inducible factors HIF-1 and HIF-2. This review summarizes several recent reports describing hypoxia-induced mechanisms of immune evasion in sarcoma and breast, colorectal, hepatocellular, prostate and uterine cancer. These studies point to several novel therapeutic approaches to improve anti-tumor immunity and increase responses to immunotherapy.