Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of haematological malignancies such as acute lymphoblastic leukaemia, B cell lymphoma and multiple myeloma
, but the ...efficacy of CAR T cell therapy in solid tumours has been limited
. This is owing to a number of factors, including the immunosuppressive tumour microenvironment that gives rise to poorly persisting and metabolically dysfunctional T cells. Analysis of anti-CD19 CAR T cells used clinically has shown that positive treatment outcomes are associated with a more 'stem-like' phenotype and increased mitochondrial mass
. We therefore sought to identify transcription factors that could enhance CAR T cell fitness and efficacy against solid tumours. Here we show that overexpression of FOXO1 promotes a stem-like phenotype in CAR T cells derived from either healthy human donors or patients, which correlates with improved mitochondrial fitness, persistence and therapeutic efficacy in vivo. This work thus reveals an engineering approach to genetically enforce a favourable metabolic phenotype that has high translational potential to improve the efficacy of CAR T cells against solid tumours.
Prostate cancer is caused by genomic aberrations in normal epithelial cells, however clinical translation of findings from analyses of cancer cells alone has been very limited. A deeper understanding ...of the tumour microenvironment is needed to identify the key drivers of disease progression and reveal novel therapeutic opportunities.
In this study, the experimental enrichment of selected cell-types, the development of a Bayesian inference model for continuous differential transcript abundance, and multiplex immunohistochemistry permitted us to define the transcriptional landscape of the prostate cancer microenvironment along the disease progression axis. An important role of monocytes and macrophages in prostate cancer progression and disease recurrence was uncovered, supported by both transcriptional landscape findings and by differential tissue composition analyses. These findings were corroborated and validated by spatial analyses at the single-cell level using multiplex immunohistochemistry.
This study advances our knowledge concerning the role of monocyte-derived recruitment in primary prostate cancer, and supports their key role in disease progression, patient survival and prostate microenvironment immune modulation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Sarcomas are a diverse group of bone and soft tissue tumors that account for over 10% of childhood cancers. Outcomes are particularly poor for children with refractory, relapsed, or metastatic ...disease. Chimeric antigen receptor T (CAR T) cells are an exciting form of adoptive cell therapy that potentially offers new hope for these children. In early trials, promising outcomes have been achieved in some pediatric patients with sarcoma. However, many children do not derive benefit despite significant expression of the targeted tumor antigen. The success of CAR T cell therapy in sarcomas and other solid tumors is limited by the immunosuppressive tumor microenvironment (TME). In this review, we provide an update of the CAR T cell therapies that are currently being tested in pediatric sarcoma clinical trials, including those targeting tumors that express HER2, NY-ESO, GD2, EGFR, GPC3, B7-H3, and MAGE-A4. We also outline promising new CAR T cells that are in pre-clinical development. Finally, we discuss strategies that are being used to overcome tumor-mediated immunosuppression in solid tumors; these strategies have the potential to improve clinical outcomes of CAR T cell therapy for children with sarcoma.
Patients who receive chimeric antigen receptor (CAR)-T cells that are enriched in memory T cells exhibit better disease control as a result of increased expansion and persistence of the CAR-T cells. ...Human memory T cells include stem-like CD8
memory T cell progenitors that can become either functional stem-like T (T
) cells or dysfunctional T progenitor exhausted (T
) cells. To that end, we demonstrated that T
cells were less abundant in infused CAR-T cell products in a phase 1 clinical trial testing Lewis Y-CAR-T cells (NCT03851146), and the infused CAR-T cells displayed poor persistence in patients. To address this issue, we developed a production protocol to generate T
-like CAR-T cells enriched for expression of genes in cell replication pathways. Compared with conventional CAR-T cells, T
-like CAR-T cells had enhanced proliferative capacity and increased cytokine secretion after CAR stimulation, including after chronic CAR stimulation in vitro. These responses were dependent on the presence of CD4
T cells during T
-like CAR-T cell production. Adoptive transfer of T
-like CAR-T cells induced better control of established tumors and resistance to tumor rechallenge in preclinical models. These more favorable outcomes were associated with increased persistence of T
-like CAR-T cells and an increased memory T cell pool. Last, T
-like CAR-T cells and anti-programmed cell death protein 1 (PD-1) treatment eradicated established tumors, and this was associated with increased tumor-infiltrating CD8
CAR
T cells producing interferon-γ. In conclusion, our CAR-T cell protocol generated T
-like CAR-T cells with enhanced therapeutic efficacy, resulting in increased proliferative capacity and persistence in vivo.
Background
In esophageal cancer (EC), there is a paucity of knowledge regarding the interplay between the tumor immune microenvironment and response to neoadjuvant treatment and, therefore, which ...factors may influence outcomes. Thus, our goal was to investigate the changes in the immune microenvironment with neoadjuvant treatment in EC by assessing the expression of immune related genes and their association with prognosis.
Methods
We examined the transcriptome of paired pre- and post-neoadjuvant treated EC specimens. Based on these findings, we validated the presence of tumor-infiltrating neutrophils using CD15
+
immunohistochemistry in a discovery cohort of patients with residual pathologic disease. We developed a nomogram as a predictor of progression-free survival (PFS) incorporating the variables CD15
+
cell count, tumor regression grade, and tumor grade.
Results
After neoadjuvant treatment, there was an increase in genes related to myeloid cell differentiation and a poor prognosis associated with high neutrophil (CD15
+
) counts. Our nomogram incorporating CD15
+
cell count was predictive of PFS with a C-index of 0.80 (95% confidence interval CI 0.68–0.9) and a concordance probability estimate (CPE) of 0.77 (95% CI 0.69–0.86), which indicates high prognostic ability. The C-index and CPE of the validation cohort were 0.81 (95% CI 0.69–0.91) and 0.78 (95% CI 0.7–0.86), respectively.
Conclusions
Our nomogram incorporating CD15
+
cell count can potentially be used to identify patients at high risk of recurrent disease and thus stratify patients who will benefit most from adjuvant treatment.
Tumor-infiltrating lymphocytes (TILs) are an important prognostic indicator in melanoma and play a key role in the patient's response to immune checkpoint blockade. However, until recently, it was ...not possible to combine multi-parameter markers to define the TILs and their histological context. Multiplex immunohistochemistry (mIHC) is a new technology which addresses this issue and enables simultaneous detection of melanoma and multiple immune subsets in formalin fixed paraffin embedded tissue. Following antigen retrieval, melanoma tissue sections are stained by OPAL on an autostainer, including serial rounds of epitope labelling with monoclonal antibodies followed by tyramide signal amplification (TSA). The stained tissue sections are then imaged on the Vectra instrument, and digital images are processed by analysis software (inForm and HALO) to derive tissue segmentation and immune subset densities within the tumor and tumor stroma. Spatial relationships between immune cells and tumor cells are then analyzed using a novel R algorithm. Taken together, multiplex IHC describes the histological context of the immune system in melanoma. The data is objective and allows for characterization of individual melanomas as T cell inflamed (hot), immune excluded, or no immune cells (cold).
Summary
Richter syndrome (RS), an aggressive lymphoma occurring in the context of chronic lymphocytic leukaemia/small lymphocytic lymphoma, is associated with poor prognosis when treated with ...conventional immunochemotherapy, therefore, improved treatments are required. Immune checkpoint blockade has shown efficacy in some B‐cell malignancies and modest responses in early clinical trials for RS. We investigated the immune checkpoint profile of RS as a basis to inform rational therapeutic investigations in RS.
Formalin‐fixed, paraffin‐embedded biopsies of RS (n = 19), de novo diffuse large B‐cell lymphoma (DLBCL; n = 58), transformed indolent lymphomas (follicular tFL, n = 16; marginal zone tMZL, n = 24) and non‐transformed small lymphocytic lymphoma (SLL; n = 15) underwent gene expression profiling using the NanoString Human Immunology panel. Copy number assessment was performed using next‐generation sequencing. Immunohistochemistry (IHC) for LAG3 and PD‐1 was performed.
LAG3 gene expression was higher in RS compared to DLBCL (P = 0·0002, log2FC 1·96), tFL (P < 0·0001, log2FC 2·61), tMZL (P = 0·0004, log2FC 1·79) and SLL (P = 0·0057, log2FC 1·45). LAG3 gene expression correlated with the gene expression of human leukocyte antigen Class I and II, and related immune genes and immune checkpoints. IHC revealed LAG3 protein expression on both malignant RS cells and tumour‐infiltrating lymphocytes. Our findings support the investigation of LAG3 inhibition to enhance anti‐tumour responses in RS.
N-methyl-2-pyrrolidone (NMP) is a common solvent and drug vehicle. We discovered unexpected antineoplastic and immunomodulatory activity of NMP in a cMYC-driven myeloma model. Coincident to this, NMP ...was identified as an acetyllysine mimetic and candidate bromodomain ligand. Accordingly, NMP-treated cells demonstrated transcriptional overlap with BET-bromodomain inhibition, including downregulation of cMYC and IRF4. NMP’s immunomodulatory activity occurred at sub-BET inhibitory concentrations, and, despite phenotypic similarities to lenalidomide, its antimyeloma activity was independent of the IMiD targets cereblon and Ikaros-1/3. Thus, low-affinity yet broad-spectrum bromodomain inhibition by NMP mediates biologically potent, cereblon-independent immunomodulation and at higher doses targets malignant cells directly via BET antagonism. These data reveal that NMP is a functional acetyllysine mimetic with pleotropic antimyeloma and immunomodulatory activities. Our studies highlight the potential therapeutic benefits of NMP, the consequences of current human NMP exposures, and the need for reassessment of scientific literature where NMP was used as an “inert” drug-delivery vehicle.
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•NMP functions as a nonselective acetyllysine mimetic and bromodomain ligand•NMP is a biologically potent, cereblon-independent immunomodulator•Bromodomain inhibitors and IMiDs have highly convergent gene expression signatures•Common NMP exposures occur at bromodomain-inhibitory concentrations
N-methyl-2-pyrrolidone (NMP) is an industrial solvent and pharmacological delivery vehicle. Shortt et al. now find unexpected immunostimulatory, anti-inflammatory, and antimyeloma activity of NMP. Subsequent experiments reveal that NMP is an acetylated lysine mimetic and inhibitor of bromodomain-containing histone “reader” proteins. Low NMP concentrations exhibited immunomodulatory properties reminiscent of structurally unrelated thalidomide analogs. Higher NMP doses directly downregulated critical myeloma oncogenes, including cMYC and IRF4. The potential effect of exposure to NMP requires urgent reassessment.
Recent developments in cancer immunotherapy promise better outcomes for cancer patients, although clinical trials for difficult to treat cancers such as malignant brain cancer present special ...challenges, showing little response to first generation immunotherapies. Reasons for differences in immunotherapy response in some cancer types are likely due to the nature of tumor microenvironment, which harbors multiple cell types which interact with tumor cells to establish immunosuppression. The cell types which appear to hold the key in regulating tumor immunosuppression are the tumor-infiltrating immune cells. The current standard treatment for difficult to treat cancer, including the most malignant brain cancer, glioblastoma, continues to offer a bleak outlook for patients. Immune-profiling and correlation with pathological and clinical data will lead to a deeper understanding of the tumor immune microenvironment and contribute toward the selection, optimization and development of novel precision immunotherapies. Here, we review the current understanding of the tumor microenvironmental landscape in glioblastoma with a focus on next-generation technologies including multiplex immunofluorescence and computational approaches to map the brain tumor microenvironment to decipher the role of the immune system in this lethal malignancy.
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