ABSTRACT
Melanoma metastases can be categorized by gene expression for the presence of a T-cell-inflamed tumor microenvironment, which correlates with clinical efficacy of immunotherapies. T cells frequently recognize mutational antigens corresponding to nonsynonymous somatic mutations (NSSMs), and in some cases shared differentiation or cancer-testis antigens. Therapies are being pursued to trigger immune infiltration into non-T-cell-inflamed tumors in the hope of rendering them immunotherapy responsive. However, whether those tumors express antigens capable of T-cell recognition has not been explored. To address this question, 266 melanomas from The Cancer Genome Atlas (TCGA) were categorized by the presence or absence of a T-cell-inflamed gene signature. These two subsets were interrogated for cancer-testis, differentiation, and somatic mutational antigens. No statistically significant differences were observed, including density of NSSMs. Focusing on hypothetical HLA-A2+ binding scores, 707 peptides were synthesized, corresponding to all identified candidate neoepitopes. No differences were observed in measured HLA-A2 binding between inflamed and noninflamed cohorts. Twenty peptides were randomly selected from each cohort to evaluate priming and recognition by human CD8+ T cells in vitro with 25% of peptides confirmed to be immunogenic in both. A similar gene expression profile applied to all solid tumors of TCGA revealed no association between T-cell signature and NSSMs. Our results indicate that lack of spontaneous immune infiltration in solid tumors is unlikely due to lack of antigens. Strategies that improve T-cell infiltration into tumors may therefore be able to facilitate clinical response to immunotherapy once antigens become recognized.
Subject(s)
Antigens, Neoplasm/immunology , Lymphocytes, Tumor-Infiltrating/physiology , Melanoma/immunology , Skin Neoplasms/immunology , T-Lymphocytes/physiology , Antigens, Neoplasm/metabolism , Gene Expression , HLA-A Antigens/genetics , HLA-A Antigens/metabolism , Humans , Melanoma/pathology , Skin Neoplasms/pathology , Tumor MicroenvironmentABSTRACT
There have been widespread concerns about solute transport problems in fractured media, e.g. the disposal of high-level radioactive waste in geological fractured rocks. Numerical simulation of particle tracking is gradually being employed to address these issues. Traditional predictions of radioactive waste transport using discrete fracture network (DFN) models often consider one particular realization of the fracture distribution based on fracture statistic features. This significantly underestimates the uncertainty of the risk of radioactive waste deposit evaluation. To adequately assess the uncertainty during the DFN modeling in a potential site for the disposal of high-level radioactive waste, this paper utilized the probabilistic distribution method (PDM). The method was applied to evaluate the risk of nuclear waste deposit in Beishan, China. Moreover, the impact of the number of realizations on the simulation results was analyzed. In particular, the differences between the modeling results of one realization and multiple realizations were demonstrated. Probabilistic distributions of 20 realizations at different times were also obtained. The results showed that the employed PDM can be used to describe the ranges of the contaminant particle transport. The high-possibility contaminated areas near the release point were more concentrated than the farther areas after 5E6 days, which was 25,400 m2.
Subject(s)
Radioactive Waste/analysis , China , Geology , Models, Statistical , Radioactive Waste/statistics & numerical data , Refuse DisposalABSTRACT
BACKGROUND: Aberrant Notch activation confers a proliferative advantage to many human tumors, including melanoma. This phase 2 trial assessed the antitumor activity of RO4929097, a gamma-secretase inhibitor of Notch signaling, with respect to the progression-free and overall survival of patients with advanced melanoma. METHODS: Chemotherapy-naive patients with metastatic melanoma of cutaneous or unknown origin were treated orally with RO4929097 at a dose of 20 mg daily 3 consecutive days per week. A 2-step accrual design was used with an interim analysis of the first 32 patients and with continuation of enrollment if 4 or more of the 32 patients responded. RESULTS: Thirty-six patients from 23 institutions were enrolled; 32 patients were evaluable. RO4929097 was well tolerated, and most toxicities were grade 1 or 2. The most common toxicities were nausea (53%), fatigue (41%), and anemia (22%). There was 1 confirmed partial response lasting 7 months, and there were 8 patients with stable disease lasting at least through week 12, with 1 of these continuing for 31 months. The 6-month progression-free survival rate was 9% (95% confidence interval [CI], 2%-22%), and the 1-year overall survival rate was 50% (95% CI, 32%-66%). Peripheral blood T-cell assays showed no significant inhibition of the production of interleukin-2, a surrogate pharmacodynamic marker of Notch inhibition, and this suggested that the drug levels were insufficient to achieve Notch target inhibition. CONCLUSIONS: RO4929097 showed minimal clinical activity against metastatic melanoma in this phase 2 trial, possibly because of inadequate exposure to therapeutic drug levels. Although Notch inhibition remains a compelling target in melanoma, the results do not support further investigation of RO4929097 with this dose and schedule.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Benzazepines/therapeutic use , Melanoma/drug therapy , Adult , Aged , Aged, 80 and over , Amyloid Precursor Protein Secretases/metabolism , Disease-Free Survival , Enzyme Inhibitors/therapeutic use , Female , Humans , Male , Melanoma/immunology , Melanoma/metabolism , Melanoma/pathology , Middle Aged , Neoplasm Metastasis , Receptors, Notch/genetics , Receptors, Notch/metabolism , Survival Rate , T-Lymphocytes/immunologyABSTRACT
PTEN is thought to play a critical role in T cell activation by negatively regulating the PI3K signaling pathway important for cellular activation, growth, and proliferation. To directly eliminate PTEN in postthymic T cells for studies of functional effects, we used CAR transgenic × PTEN(flox/flox) mice, which enabled gene deletion using a Cre adenovirus in vitro. These mice were also immunized to generate stable Th1 clones that could have PTEN deleted when desired. PTEN-deleted T cells exhibited enhanced IL-2 production, proliferation, and Akt phosphorylation upon TCR/CD28 engagement, whereas T cell survival was not potentiated. Gene expression profiling revealed a small subset of induced genes that were augmented upon PTEN deletion. However, PTEN-deficient T cells still required CD28 costimulation for IL-2 production and remained susceptible to anti-CD3-induced anergy. The absence of PTEN within the CD8 T cell compartment led to markedly increased cytolytic activity following an allogeneic MLR in vitro, without increasing autologous MLR activity. Our results indicate that deletion of PTEN can augment the activation of postthymic T cells but does not mediate CD28 independence or anergy resistance. Nonetheless, PTEN inhibition may be a viable target for immune potentiation owing to increased cytokine production by activated CD4(+) cells and increased cytotoxicity by CD8(+) T cells.
Subject(s)
CD28 Antigens/immunology , Clonal Anergy , PTEN Phosphohydrolase/immunology , Receptors, Antigen, T-Cell/immunology , T-Lymphocyte Subsets/immunology , Animals , Cell Division , Cells, Cultured , Cytokines/biosynthesis , Cytokines/genetics , Cytotoxicity, Immunologic , Gene Deletion , Gene Expression Profiling , Gene Expression Regulation/immunology , Lymphocyte Activation , Lymphocyte Culture Test, Mixed , Mice , Mice, Inbred C57BL , Oligonucleotide Array Sequence Analysis , PTEN Phosphohydrolase/deficiency , PTEN Phosphohydrolase/genetics , Phosphorylation , Protein Processing, Post-Translational , Proto-Oncogene Proteins c-akt/metabolism , Recombinant Fusion Proteins/immunology , Transduction, GeneticABSTRACT
Thermal treatment can be an effective method for soil remediation, and numerical models play a crucial role in elucidating the underlying processes that affect efficacy. In this study, experiments were conducted to examine the low-temperature thermal treatment for removing n-hexane and n-octane from soil. The results showed that the removal of two alkanes followed the pseudo-first-order kinetics. Additionally, a quantitative relationship between kinetics constant and temperature was established. Based on experimental results, a simple mathematical model was presented via COMSOL Multiphysics 6.0. The processes considered in the model incorporated conductive and convective heat transfer, the vaporization latent heat, and the removal of organic contaminants which was quantified using an advection-dispersion equation combined with a pseudo-first-order kinetic. The developed model was first validated by a thermal treatment in a soil column, demonstrating conformity with the measured temperature and concentration values. Subsequently, the temporal and spatial changes in soil temperature and contaminant levels were evaluated for different heating temperatures. It was found that thermal conduction dominated heat transfer, whereas thermal convection caused by the migration of liquid water intensified when the temperature was higher than the boiling point. The completion time exhibited a correlation with the heating temperature. It was predicted that the time required to achieve a 90% removal efficiency could be shortened from 14 h to 9.5 h by elevating the heating temperature from 80 â to 120 â. The study also investigated the impact of the initial water content on heat transfer. It was observed that the saturated soil showed the slowest heating rate and the longest boiling stage.
ABSTRACT
The cellular source of positive signals that reinvigorate T cells within the tumor microenvironment (TME) for the therapeutic efficacy of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade has not been clearly defined. We now show that Batf3-lineage dendritic cells (DCs) are essential in this process. Flow cytometric analysis, gene-targeted mice, and blocking antibody studies revealed that 4-1BBL is a major positive co-stimulatory signal provided by these DCs within the TME that translates to CD8+ T cell functional reinvigoration and tumor regression. Immunofluorescence and spatial transcriptomics on human tumor samples revealed clustering of Batf3+ DCs and CD8+ T cells, which correlates with anti-PD-1 efficacy. In addition, proximity to Batf3+ DCs within the TME is associated with CD8+ T cell transcriptional states linked to anti-PD-1 response. Our results demonstrate that Batf3+ DCs within the TME are critical for PD-1/PD-L1 blockade efficacy and indicate a major role for the 4-1BB/4-1BB ligand (4-1BBL) axis during this process.
Subject(s)
B7-H1 Antigen , Basic-Leucine Zipper Transcription Factors , CD8-Positive T-Lymphocytes , Dendritic Cells , Programmed Cell Death 1 Receptor , Repressor Proteins , Tumor Microenvironment , Animals , Humans , Mice , 4-1BB Ligand/metabolism , 4-1BB Ligand/genetics , B7-H1 Antigen/metabolism , Basic-Leucine Zipper Transcription Factors/metabolism , Basic-Leucine Zipper Transcription Factors/genetics , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cell Line, Tumor , Dendritic Cells/metabolism , Dendritic Cells/immunology , Immune Checkpoint Inhibitors/pharmacology , Mice, Inbred C57BL , Programmed Cell Death 1 Receptor/metabolism , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Repressor Proteins/metabolism , Signal Transduction , Tumor Necrosis Factor Receptor Superfamily, Member 9/metabolismABSTRACT
Animal experiments are important in trauma-related studies because they simulate in vivo effects. Rodents are a good choice for preparing trauma models; however, contractile healing in rodents results in a healing pattern that differs considerably from that in humans. Therefore, this study developed a new rodent model that avoids contractile healing of the skin around the wound using an anticontraction ring, and the skin in the wound's center remains intact and acts as a source for epithelialized diffusion healing. Cell proliferation, migration, revascularization, and collagen secretion did not differ between the novel and conventional full-skin defect trauma models. However, the healing rate at various stages significantly differed between the 2 groups owing to differences in the healing patterns. And without effective treatment, the experimental group cannot heal. The stabilities of the novel and conventional methods were good regardless of operator or batch. In summary, this new animal trauma model provides a stable experimental environment similar to that in humans, which may promote trauma-related research.
Subject(s)
Disease Models, Animal , Wound Healing , Animals , Wound Healing/physiology , Rats , Re-Epithelialization , Male , Rats, Sprague-Dawley , Cell Proliferation , Skin/injuriesABSTRACT
Most diffuse large B-cell lymphoma (DLBCL) patients treated with bispecific antibodies (BsAb) or chimeric antigen receptor (CAR) T cells fail to achieve durable treatment responses, underscoring the need for a deeper understanding of mechanisms that regulate the immune environment and response to treatment. Here, an integrative, multi-omic approach was employed to characterize DLBCL immune environments, which effectively segregated DLBCLs into four quadrants - termed DLBCL-immune quadrants (IQ) - defined by cell-of-origin and immune-related gene set expression scores. Recurrent genomic alterations were enriched in each IQ, suggesting that lymphoma cell-intrinsic alterations contribute to orchestrating unique DLBCL immune environments. In relapsed/refractory DLBCL patients, DLBCL-IQ assignment correlated significantly with clinical benefit with the CD20 x CD3 BsAb, mosunetuzumab, but not with CD19-directed CAR T cells. DLBCL-IQ provides a new framework to conceptualize the DLBCL immune landscape and uncovers the differential impact of the endogenous immune environment on outcomes to BsAb and CAR T cell treatment.
ABSTRACT
The treatment of dense non-aqueous phase liquid (DNAPL) source zones is challenging, particularly in heterogeneous media. Thermal conductive heating (TCH) has the potential to treat DNAPL source zones for its ability to enhance mass transfer. This study uses numerical modeling combined with Monte Carlo simulation to examine the influence of heterogeneity of the permeability field on the DNAPL distribution and TCH remediation. It is found that the longer horizontal correlation length of high-permeable clay lens would contribute to accelerate multiphase convection and then heat conduction in horizontal direction. The presence of DNAPL (both in NAPL phase and dissolved), pressure, and permeability are all contributory factors to phase change. Realizations with shorter horizontal correlation lengths always have a larger vertical spreading of DNAPL. As a shallow vapor extraction well was applied in this study, higher TCE removal rate can be obtained in the realizations with a shorter horizontal correlation length when NAPL phase of TCE is existed in the domain.
Subject(s)
Heating , Water Pollutants, Chemical , Soil , Computer Simulation , Clay , Water Pollutants, Chemical/analysisABSTRACT
BACKGROUNDWe previously demonstrated the safety of stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) in patients with advanced solid tumors. This phase I clinical trial was expanded to study the safety of partial tumor irradiation (partial-Rx). We assessed irradiated local failure (LF) and clinical outcomes with correlations to biomarkers including CD8+ T cell radiomics score (RS) and circulating cytokines.METHODSPatients received SBRT to 2-4 metastases and pembrolizumab for up to 7 days after SBRT. Tumors measuring up to 65 cc received the full radiation dose (complete-Rx), whereas tumors measuring more than 65 cc received partial-Rx. Landmark analysis was used to assess the relationship between tumor response and overall survival (OS). Multivariable analysis was performed for RS and circulating cytokines.RESULTSIn the combined (expansion plus original) cohort, 97 patients (219 metastases) were analyzed and received SBRT+P. Forty-six (47%) patients received at least 1 partial-Rx treatment. There were 7 (7.2%)dose-limiting toxicities (DLTs). 1-year LF was 7.6% overall, and 13.3% and 5.4% for partial-Rx and complete-Rx tumors, respectively (HR 2.32, 95% CI 0.90-5.97, P = 0.08). The overall, unirradiated, and irradiated objective response rates were 22%, 12%, and 34%, respectively. Irradiated tumor response to SBRT+P was associated with prolonged OS; 1-year OS was 71% (responders), 42% (mixed-responders), and 0% (nonresponders) (P < 0.01). High-RS was significantly associated with improved LF, progression-free survival (PFS), and OS. Elevated circulating IL-8 was independently associated with inferior PFS and OS.CONCLUSIONSBRT+P is safe in patients with large, advanced solid tumors. Additional studies are warranted to assess noninferiority of complete versus partial irradiation of tumors in the setting of immunotherapy.TRIAL REGISTRATIONClinicaltrials.gov NCT02608385FUNDINGMerck Investigator Studies Program; Hillman Fellows for Innovative Cancer Research Program; NIH grants UM1CA186690-06, P50CA254865-01A1, P30CA047904-32, and R01DE031729-01A1.
Subject(s)
Neoplasms , Radiosurgery , Humans , Antibodies, Monoclonal, Humanized/adverse effects , Cytokines , Neoplasms/drug therapy , Neoplasms/radiotherapy , Radiosurgery/adverse effectsABSTRACT
BACKGROUND: PD-1 checkpoint blockade therapy (CBT) has greatly benefited patients with select solid tumors and lymphomas but has limited efficacy against diffuse large B-cell lymphoma (DLBCL). Because numerous inhibitory checkpoint receptors have been implicated in driving tumor-specific T cell dysfunction, we hypothesized that combinatorial CBT would enhance the activity of anti-PD-1-based therapy in DLBCL. T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is a coinhibitory receptor expressed on dysfunctional tumor-infiltrating T cells, and TIGIT blockade has demonstrated encouraging activity in combination with PD-1 blockade in murine tumor models and in clinical studies. However, the degree to which TIGIT mediates T cell dysfunction in DLBCL has not been fully explored. RESULTS: Here, we demonstrate that TIGIT is broadly expressed on lymphoma-infiltrating T cells (LITs) across a variety of human lymphomas and is frequently coexpressed with PD-1. TIGIT expression is particularly common on LITs in DLBCL, where TIGIT+ LITs often form distinct cellular communities and exhibit significant contact with malignant B cells. TIGIT+/PD-1+ LITs from human DLBCL and murine lymphomas exhibit hypofunctional cytokine production on ex vivo restimulation. In mice with established, syngeneic A20 B-cell lymphomas, TIGIT or PD-1 mono-blockade leads to modest delays in tumor outgrowth, whereas PD-1 and TIGIT co-blockade results in complete rejection of A20 lymphomas in most mice and significantly prolongs survival compared with mice treated with monoblockade therapy. CONCLUSIONS: These results provide rationale for clinical investigation of TIGIT and PD-1 blockade in lymphomas, including DLBCL.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Programmed Cell Death 1 Receptor , Humans , Animals , Mice , Receptors, Immunologic/metabolism , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/pathologyABSTRACT
Drought-rehydration irrigation has an enhancing impact on rice yield, but the current research on its yield-increasing effect is mainly experimental and empirical, lacking mechanism theoretical support. Image-based machine vision is rapidly developing and can estimate crop physical and chemical properties. A novel image processing method has been purposefully carried out to detect the real-time response shape of rice drought-rehydration. By application of this method, two new types of morphological descriptors were proposed to characterize and quantify the vertical phenotypic heterogeneity of rice, in which the relative height of the plant centroid (RHC) locates the growth focus, while the leaf angle distribution model describes the vertical characteristics of the leaf phenotypic traits. We verified the response of the vertical traits to different water treatments through designed experiments. The results showed that the RHC and leaf angle distribution parameters followed divergent trends under water stress, reflecting the drought characteristics of rice at different growth stages. The newly developed indicators were sensitive to drought response at specific growth stages and also efficient for evaluating rice growth, including determination of radiation interception capacity and assessment of nutrient accumulation. Furthermore, through the measurement and analysis of vertical structural traits, we found that a short-term water deficit and reasonable rehydration during the rice heading period could help to extend the spike-growing time and improve photosynthetic efficiency, thus benefiting yield formation.
ABSTRACT
Gentiopicroside (GEN) is a secoiridoid glycosides isolated from a traditional Chinese medicine Gentiana macrophylla Pall.. It exhibits potential activities in the treatment of inflammatory diseases. Here, we investigated whether GEN had the anti-rheumatoid arthritic activities in a model of rheumatoid arthritis, and explored its molecular mechanism. In vivo, the male C57BL/6J mice were injected chicken type II collagen to induce the animal model (collagen-induced arthritis, CIA). In vitro, we performed the research in rheumatoid fibroblast-like synoviocytes (FLS). In our study, it was innovatively authenticated that GEN treatment could not only reduce synovitis and inhibit the proliferation of RA FLS, but also relieve cartilage damage in CIA modal. More importantly, we firstly demonstrated that GEN treatment lessened the pain behaviors of CIA mice. In vivo and in vitro experiments confirmed that CD147 was the main target of GEN in attenuating RA symptoms for the first time. Next, we identified the downstream signaling pathway of CD147, and proved that the anti-RA effects of GEN were mediated by down-regulating the expression of p38, IκBα and p65 in vivo and in vitro assays. In conclusion, the data of this manuscript suggested that GEN treatment attenuated synovitis and cartilage destruction in CIA mice; the inhibitory effects on MMP secretion and the anti-rheumatic effects of GEN might be regulated by the CD147/p38/ NF-κB pathway. Accordingly, we found that GEN has the potential therapeutic effects for RA.
Subject(s)
Arthritis, Experimental , Synoviocytes , Synovitis , Animals , Arthritis, Experimental/metabolism , Basigin/metabolism , Cells, Cultured , Fibroblasts , Iridoid Glucosides , MAP Kinase Signaling System , Male , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , Synovial MembraneABSTRACT
Immune checkpoint blockade is therapeutically successful for many patients across multiple cancer types. However, immune-related adverse events (irAE) frequently occur and can sometimes be life threatening. It is critical to understand the immunologic mechanisms of irAEs with the goal of finding novel treatment targets. Herein, we report our analysis of tissues from patients with irAE dermatitis using multiparameter immunofluorescence (IF), spatial transcriptomics, and RNA in situ hybridization (RISH). Skin psoriasis cases were studied as a comparison, as a known Th17-driven disease, and colitis was investigated as a comparison. IF analysis revealed that CD4+ and CD8+ tissue-resident memory T (TRM) cells were preferentially expanded in the inflamed portion of skin in cutaneous irAEs compared with healthy skin controls. Spatial transcriptomics allowed us to focus on areas containing TRM cells to discern functional phenotype and revealed expression of Th1-associated genes in irAEs, compared with Th17-asociated genes in psoriasis. Expression of PD-1, CTLA-4, LAG-3, and other inhibitory receptors was observed in irAE cases. RISH technology combined with IF confirmed expression of IFNγ, CXCL9, CXCL10, and TNFα in irAE dermatitis, as well as IFNγ within TRM cells specifically. The Th1-skewed phenotype was confirmed in irAE colitis cases compared with healthy colon.
Subject(s)
Colitis , Dermatitis , Psoriasis , CTLA-4 Antigen , Colitis/chemically induced , Cytokines/metabolism , Humans , Immune Checkpoint Inhibitors , Memory T Cells , Programmed Cell Death 1 Receptor , RNA , Tumor Necrosis Factor-alphaABSTRACT
BACKGROUND: Patients with cancer were excluded from phase 3 COVID-19 vaccine trials, and the immunogenicity and side effect profiles of these vaccines in this population is not well understood. Patients with cancer can be immunocompromised from chemotherapy, corticosteroids, or the cancer itself, which may affect cellular and/or humoral responses to vaccination. PD-1 is expressed on T effector cells, T follicular helper cells and B cells, leading us to hypothesize that anti-PD-1 immunotherapies may augment antibody or T cell generation after vaccination. METHODS: Antibodies to the SARS-CoV-2 receptor binding domain (RBD) and spike protein were assessed in patients with cancer (n=118) and healthy donors (HD, n=22) after 1, 2 or 3 mRNA vaccine doses. CD4+ and CD8+ T cell reactivity to wild-type (WT) or B.1.617.2 (delta) spike peptides was measured by intracellular cytokine staining. RESULTS: Oncology patients without prior COVID-19 infections receiving immunotherapy (n=36), chemotherapy (n=15), chemoimmunotherapy (n=6), endocrine or targeted therapies (n=6) and those not on active treatment (n=26) had similar RBD and Spike IgG antibody titers to HDs after two vaccinations. Contrary to our hypothesis, PD-1 blockade did not augment antibody titers or T cell responses. Patients receiving B-cell directed therapies (n=14) including anti-CD20 antibodies and multiple myeloma therapies had decreased antibody titers, and 9/14 of these patients were seronegative for RBD antibodies. No differences were observed in WT spike-reactive CD4+ and CD8+ T cell generation between treatment groups. 11/13 evaluable patients seronegative for RBD had a detectable WT spike-reactive CD4+ T cell response. T cells cross-reactive against the B.1.617.2 variant spike peptides were detected in 31/59 participants. Two patients with prior immune checkpoint inhibitor-related adrenal insufficiency had symptomatic hypoadrenalism after vaccination. CONCLUSIONS: COVID-19 vaccinations are safe and immunogenic in patients with solid tumors, who developed similar antibody and T cell responses compared with HDs. Patients on B-cell directed therapies may fail to generate RBD antibodies after vaccination and should be considered for prophylactic antibody treatments. Many seronegative patients do develop a T cell response, which may have an anti-viral effect. Patients with pre-existing adrenal insufficiency may need to take stress dose steroids during vaccination to avoid adrenal crisis.
Subject(s)
COVID-19 Vaccines , COVID-19 , Neoplasms , Adrenal Insufficiency/complications , Antibodies, Viral/blood , Antibody Formation , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Humans , Immunity, Cellular , Neoplasms/complications , Neoplasms/drug therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , SARS-CoV-2 , T-Lymphocytes/immunology , Vaccination , Vaccines, Synthetic , mRNA Vaccines/immunologyABSTRACT
Over 500 clinical trials are investigating combination radiotherapy and immune checkpoint blockade (ICB) as cancer treatments; however, the majority of trials have found no positive interaction. Here we perform a comprehensive molecular analysis of a randomized phase I clinical trial of patients with non-small cell lung cancer (NSCLC) treated with concurrent or sequential ablative radiotherapy and ICB. We show that concurrent treatment is superior to sequential treatment in augmenting local and distant tumor responses and in improving overall survival in a subset of patients with immunologically cold, highly aneuploid tumors, but not in those with less aneuploid tumors. In addition, radiotherapy alone decreases intratumoral cytotoxic T cell and adaptive immune signatures, whereas radiotherapy and ICB upregulates key immune pathways. Our findings challenge the prevailing paradigm that local ablative radiotherapy beneficially stimulates the immune response. We propose the use of tumor aneuploidy as a biomarker and therapeutic target in personalizing treatment approaches for patients with NSCLC treated with radiotherapy and ICB.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/therapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Immune Checkpoint Inhibitors , Lung Neoplasms/therapy , Lung Neoplasms/drug therapy , Biomarkers , Combined Modality TherapyABSTRACT
BACKGROUND: Tumor-infiltrating CD8+ T cells and neoantigens are predictors of a favorable prognosis and response to immunotherapy with checkpoint inhibitors in many types of adult cancer, but little is known about their role in pediatric malignancies. Here, we analyzed the prognostic strength of T cell-inflamed gene expression and neoantigen load in high-risk neuroblastoma. We also compared transcriptional programs in T cell-inflamed and non-T cell-inflamed high-risk neuroblastomas to investigate possible mechanisms of immune exclusion. METHODS: A defined T cell-inflamed gene expression signature was used to categorize high-risk neuroblastomas in the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program (n=123), and the Gabriella Miller Kids First (GMKF) program (n=48) into T cell-inflamed, non-T cell-inflamed, and intermediate groups. Associations between the T cell-inflamed and non-T cell-inflamed group, MYCN amplification, and survival were analyzed by Cox proportional hazards models. Additional survival analysis was conducted after integrating neoantigen load predicted from somatic mutations. Pathways activated in non-T cell-inflamed relative to T cell-inflamed tumors were analyzed using causal network analysis. RESULTS: Patients with T cell-inflamed high-risk tumors showed improved overall survival compared with those with non-T cell-inflamed tumors (p<0.05), independent of MYCN amplification status, in both TARGET and GMKF cohorts. Higher neoantigen load was also associated with better event-free and overall survival (p<0.005) and was independent of the T cell-inflamed signature. Activation of MYCN, ASCL1, SOX11, and KMT2A transcriptional programs was inversely correlated with the T cell-inflamed signature in both cohorts. CONCLUSIONS: Our results indicate that tumors from children with high-risk neuroblastoma harboring a strong T cell-inflamed signature have a more favorable clinical outcome, and neoantigen load is a prognosis predictor, independent of T cell inflammation. Strategies to target SOX11 and other signaling pathways associated with non-T cell-inflamed tumors should be pursued as potential immune-potentiating interventions.
Subject(s)
Immunotherapy/methods , Neuroblastoma/immunology , Tumor Microenvironment/immunology , Cohort Studies , Female , Humans , Male , Neuroblastoma/mortality , Prognosis , Risk Factors , Survival AnalysisABSTRACT
Venous thromboembolism is a significant source of morbidity and mortality worldwide. Catheter-directed thrombolytics is the primary treatment used to relieve critical obstructions, though its efficacy varies based on the thrombus composition. Non-responsive portions of the specimen often remain in situ, which prohibits mechanistic investigation of lytic resistance or the development of diagnostic indicators for treatment outcomes. In this study, thrombus samples extracted from venous thromboembolism patients were analyzed ex vivo to determine their histological properties, susceptibility to lytic therapy, and imaging characteristics. A wide range of thrombus morphologies were observed, with a dependence on age and etymology of the specimen. Fibrinolytic inhibitors including PAI-1, alpha 2-antiplasmin, and TAFI were present in samples, which may contribute to the response venous thrombi to catheter-directed thrombolytics. Finally, a weak but significant correlation was observed between the response of the sample to lytic drug and its magnetic microstructure assessed with a quantitative MRI sequence. These findings highlight the myriad of changes in venous thrombi that may promote lytic resistance, and imaging metrics that correlate with treatment outcomes.
Subject(s)
Biomarkers/metabolism , Elasticity Imaging Techniques/methods , Tissue Plasminogen Activator/administration & dosage , Ultrasonography/methods , Venous Thrombosis/pathology , Fibrinolytic Agents/administration & dosage , Humans , Venous Thrombosis/drug therapy , Venous Thrombosis/metabolismABSTRACT
Uveal melanoma is a rare form of melanoma with particularly poor outcomes in the metastatic setting. In contrast with cutaneous melanoma, uveal melanoma lacks BRAF mutations and demonstrates very low response rates to immune-checkpoint blockade. Our objectives were to study the transcriptomics of metastatic uveal melanoma with the intent of assessing gene pathways and potential molecular characteristics that might be nominated for further exploration as therapeutic targets. We initially analyzed transcriptional data from The Cancer Genome Atlas suggesting PI3K/mTOR and glycolysis as well as IL6 associating with poor survival. From tumor samples collected in a prospective phase II trial (A091201), we performed a transcriptional analysis of human metastatic uveal melanoma observing a novel role for epithelial-mesenchymal transition associating with survival. Specifically, we nominate and describe initial functional validation of neuropillin-1 from uveal melanoma cells as associated with poor survival and as a mediator of proliferation and migration for uveal melanoma in vitro. These results immediately nominate potential next steps in clinical research for patients with metastatic uveal melanoma.
Subject(s)
Gene Expression Regulation, Neoplastic/genetics , Melanoma/genetics , Skin Neoplasms/genetics , Uveal Neoplasms/genetics , Humans , Melanoma/mortality , Neoplasm Metastasis , Skin Neoplasms/mortality , Survival Analysis , Transfection , Uveal Neoplasms/mortalityABSTRACT
PURPOSE: Combination of antiprogrammed cell death protein-1 (PD-1) plus anti-cytotoxic T-cell lymphocyte-4 (anti-CTLA-4) immunotherapy shows greater response rates (RRs) than anti-PD-1 antibody alone in melanoma, but RR after initial anti-PD-1 and programmed death ligand-1 (PD-L1) antibody progression awaits robust investigation. Anti-CTLA-4 antibody alone after anti-PD-1/L1 antibody progression has a historical RR of 13%. We report the results of the first prospective clinical trial evaluating ipilimumab 1 mg/kg plus pembrolizumab following progression on anti-PD-1 immunotherapy. METHODS: Patients with advanced melanoma who had progressed on anti-PD-1/L1 antibody as immediate prior therapy (including non-anti-CTLA-4 antibody combinations) were eligible. Patients received pembrolizumab 200 mg plus ipilimumab 1 mg/kg once every 3 weeks for four doses, followed by pembrolizumab monotherapy. The primary end point was RR by irRECIST. After 35 patients, the trial met the primary end point and was expanded to enroll a total of 70 patients to better estimate the RR. RESULTS: Prior treatments included 60 on anti-PD-1 antibody alone and 10 on anti-PD-1/L1 antibody-based combinations. Thirteen patients had progressed in the adjuvant setting. The median length of prior treatment with anti-PD-1/L1 antibody was 4.8 months. Response assessments included five complete and 15 partial responses, making the irRECIST RR 29% among the entire trial population. The median progression-free survival was 5.0 months, and the median overall survival was 24.7 months. The median duration of response was 16.6 months. There was no difference in median time on prior anti-PD1/L1 or time to PD1 + CTLA4 initiation between responders and nonresponders. Grade 3-4 drug-related adverse events occurred in 27% of patients. Responses occurred in PD-L1-negative, non-T-cell-inflamed, and intermediate tumor phenotypes. CONCLUSION: To our knowledge, this is the first prospective study in melanoma of pembrolizumab plus low-dose ipilimumab after anti-PD-1/L1 immunotherapy failure, demonstrating significant antitumor activity and tolerability.