Editorial: Local Immunotherapy: A Way to Convert Tumors From "Cold" to "Hot".
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ABSTRACT:
SUBMITTER: Bilusic M
PROVIDER: S-EPMC6279267 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Immunotherapies have an established role in the management of several advanced malignancies. Their responses are largely dependent on the presence of PD-L1, microsatellite instability (MSI), and high tumor mutation burden. Sarcomas are heterogenous tumors which comprise over 100 subtypes. They are broadly considered immunologically inert or "cold". Immunotherapy as monotherapy has shown interesting responses in a certain handful of subtypes, such as undifferentiated pleomorphic sarcoma, dedifferentiated and pleomorphic liposarcoma, and alveolar soft part sarcoma. However, the mechanisms of action of immunotherapy agents in several sarcoma subtypes remains unknown. Several sarcoma types such as leiomyosarcoma have been shown to have an immunosuppressive microenvironment. Early clinical studies suggest the emergence of B cell infiltration in sarcoma tumor tissues as well as the role of PD-1 and PD-L1 as biomarkers of response. Immunotherapy combinations with conventional chemotherapies, radiation therapies, tyrosine kinase inhibitors and oncolytic viruses are showing promise in turning these "cold" tumors "hot". Several novel agents as well as repurposing therapies with the potential to enhance immunotherapy responses are undergoing pre-clinical and clinical studies in other tumor types. Herein we review current clinical studies which have explored the use of immunotherapeutic agents in the management of sarcomas and discuss the challenges and future directions.
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Project description:One of the major challenges limiting the efficacy of anti-PD-1/PD-L1 therapy in nonresponding patients is the failure of T cells to penetrate the tumor microenvironment. We showed that genetic or pharmacological inhibition of Vps34 kinase activity using SB02024 or SAR405 (Vps34i) decreased the tumor growth and improved mice survival in multiple tumor models by inducing an infiltration of NK, CD8+, and CD4+ T effector cells in melanoma and CRC tumors. Such infiltration resulted in the establishment of a T cell-inflamed tumor microenvironment, characterized by the up-regulation of pro-inflammatory chemokines and cytokines, CCL5, CXCL10, and IFNγ. Vps34i treatment induced STAT1 and IRF7, involved in the up-regulation of CCL5 and CXCL10. Combining Vps34i improved the therapeutic benefit of anti-PD-L1/PD-1 in melanoma and CRC and prolonged mice survival. Our study revealed that targeting Vps34 turns cold into hot inflamed tumors, thus enhancing the efficacy of anti-PD-L1/PD-1 blockade.
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Project description:The development of immunotherapies has revolutionized intervention strategies for a variety of primary cancers. Despite this promising progress, treatment options for primary brain cancer and brain metastasis remain limited and still largely depend on surgical resection, radio- and/or chemotherapy. The paucity in the successful development of immunotherapies for brain cancers can in part be attributed to the traditional view of the brain as an immunologically privileged site. The presence of the blood-brain barrier and the absence of lymphatic drainage were believed to restrict the entry of blood-borne immune and inflammatory cells into the central nervous system (CNS), leading to an exclusion of the brain from systemic immune surveillance. However, recent insight from pre-clinical and clinical studies on the immune landscape of brain cancers challenged this dogma. Recruitment of blood-borne immune cells into the CNS provides unprecedented opportunities for the development of tumor microenvironment (TME)-targeted or immunotherapies against primary and metastatic cancers. Moreover, it is increasingly recognized that in addition to genotoxic effects, ionizing radiation represents a critical modulator of tumor-associated inflammation and synergizes with immunotherapies in adjuvant settings. This review summarizes current knowledge on the cellular and molecular identity of tumor-associated immune cells in primary and metastatic brain cancers and discusses underlying mechanisms by which ionizing radiation modulates the immune response. Detailed mechanistic insight into the effects of radiation on the unique immune landscape of brain cancers is essential for the development of multimodality intervention strategies in which immune-modulatory effects of radiotherapy are exploited to sensitize brain cancers to immunotherapies by converting immunologically "cold" into "hot" environments.
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Project description:Immunotherapy, represented by immune checkpoint inhibitors (ICIs), has greatly improved the clinical efficacy of malignant tumor therapy. ICI-mediated antitumor responses depend on the infiltration of T cells capable of recognizing and killing tumor cells. ICIs are not effective in "cold tumors", which are characterized by the lack of T-cell infiltration. To realize the full potential of immunotherapy and solve this obstacle, it is essential to understand the drivers of T-cell infiltration into tumors. We present a critical review of our understanding of the mechanisms underlying "cold tumors", including impaired T-cell priming and deficient T-cell homing to tumor beds. "Hot tumors" with significant T-cell infiltration are associated with better ICI efficacy. In this review, we summarize multiple strategies that promote the transformation of "cold tumors" into "hot tumors" and discuss the mechanisms by which these strategies lead to increased T-cell infiltration. Finally, we discuss the application of nanomaterials to tumor immunotherapy and provide an outlook on the future of this emerging field. The combination of nanomedicines and immunotherapy enhances cross-presentation of tumor antigens and promotes T-cell priming and infiltration. A deeper understanding of these mechanisms opens new possibilities for the development of multiple T cell-based combination therapies to improve ICI effectiveness.
| S-EPMC8039952 | biostudies-literature
Project description:Reprogramming the tumor microenvironment to increase immune-mediated responses is currently of intense interest. Patients with immune-infiltrated "hot" tumors demonstrate higher treatment response rates and improved survival. However, only the minority of tumors are hot, and a limited proportion of patients benefit from immunotherapies. Innovative approaches that make tumors hot can have immediate impact particularly if they repurpose drugs with additional cancer-unrelated benefits. The seasonal influenza vaccine is recommended for all persons over 6 mo without prohibitive contraindications, including most cancer patients. Here, we report that unadjuvanted seasonal influenza vaccination via intratumoral, but not intramuscular, injection converts "cold" tumors to hot, generates systemic CD8+ T cell-mediated antitumor immunity, and sensitizes resistant tumors to checkpoint blockade. Importantly, intratumoral vaccination also provides protection against subsequent active influenza virus lung infection. Surprisingly, a squalene-based adjuvanted vaccine maintains intratumoral regulatory B cells and fails to improve antitumor responses, even while protecting against active influenza virus lung infection. Adjuvant removal, B cell depletion, or IL-10 blockade recovers its antitumor effectiveness. Our findings propose that antipathogen vaccines may be utilized for both infection prevention and repurposing as a cancer immunotherapy.
| S-EPMC6969546 | biostudies-literature
Project description:We discuss how small-molecule inhibitors of the tryptophan (Trp) catabolic enzyme indoleamine 2,3-dioxygenase (IDO) represent a vanguard of new immunometabolic adjuvants to safely enhance the efficacy of cancer immunotherapy, radiotherapy, or 'immunogenic' chemotherapy by leveraging responses to tumor neoantigens. IDO inhibitors re-program inflammatory processes to help clear tumors by blunting tumor neovascularization and restoring immunosurveillance. Studies of regulatory and effector pathways illuminate IDO as an inflammatory modifier. Recent work suggests that coordinate targeting of the Trp catabolic enzymes tryptophan 2,3-dioxygenase (TDO) and IDO2 may also safely broaden efficacy. Understanding IDO inhibitors as adjuvants to turn immunologically 'cold' tumors 'hot' can seed new concepts in how to improve the efficacy of cancer therapy while limiting collateral damage.
| S-EPMC6015766 | biostudies-literature
Project description:Tumor infiltration by T cells profoundly affects cancer progression and responses to immunotherapy. However, the tumor immunosuppressive microenvironment can impair the induction, trafficking, and local activity of antitumor T cells. Here, we investigated whether intratumoral injection of virus-derived peptide epitopes could activate preexisting antiviral T cell responses locally and promote antitumor responses or antigen spreading. We focused on a mouse model of cytomegalovirus (CMV), a highly prevalent human infection that induces vigorous and durable T cell responses. Mice persistently infected with murine CMV (MCMV) were challenged with lung (TC-1), colon (MC-38), or melanoma (B16-F10) tumor cells. Intratumoral injection of MCMV-derived T cell epitopes triggered in situ and systemic expansion of their cognate, MCMV-specific CD4+ or CD8+ T cells. The MCMV CD8+ T cell epitopes injected alone provoked arrest of tumor growth and some durable remissions. Intratumoral injection of MCMV CD4+ T cell epitopes with polyinosinic acid:polycytidylic acid (pI:C) preferentially elicited tumor antigen-specific CD8+ T cells, promoted tumor clearance, and conferred long-term protection against tumor rechallenge. Notably, secondary proliferation of MCMV-specific CD8+ T cells correlated with better tumor control. Importantly, intratumoral injection of MCMV-derived CD8+ T cell-peptide epitopes alone or CD4+ T cell-peptide epitopes with pI:C induced potent adaptive and innate immune activation of the tumor microenvironment. Thus, CMV-derived peptide epitopes, delivered intratumorally, act as cytotoxic and immunotherapeutic agents to promote immediate tumor control and long-term antitumor immunity that could be used as a stand-alone therapy. The tumor antigen-agnostic nature of this approach makes it applicable across a broad range of solid tumors regardless of their origin.
| S-EPMC9245622 | biostudies-literature
Project description:NanoString pan-cancer immune panel was used to quantified the expression of 730 immune genes of 15 tumor-free TDLNs and paired tumors. FFPE slides were used to quantified the gene expression.
2024-07-29 | GSE272455 | GEO
Project description:BackgroundIn reference to previous studies, necroptosis played an important role in cancer development. Our team decided to explore the potential prognostic values of long non-coding RNAs (lncRNAs) associated with necroptosis in bladder urothelial carcinoma (BLCA) and their relationship with the tumor microenvironment (TME) and the immunotherapeutic response for accurate dose.MethodsTo obtain the required data, bladder urothelial carcinoma transcriptome data were searched from Cancer Genome Atlas (TCGA) (https://portal.gdc.cancer.gov/). We used co-expression analysis, differential expression analysis, and univariate Cox regression to screen out prognostic lncRNAs associated with necroptosis in BLCA. Then the least absolute shrinkage and selection operator (LASSO) was conducted to construct the necroptosis-associated lncRNAs model. Based on this model, we also performed the Kaplan-Meier analysis and time-dependent receiver operating characteristics (ROC) to estimate the prognostic power of risk score. Multivariate and univariate Cox regression analysis were performed to build up a nomogram. Calibration curves, and time-dependent ROC were also conducted to evaluate nomogram. Principal component analysis (PCA) revealed a difference between high- and low-risk groups. In addition, we explored immune analysis, gene set enrichment analyses (GSEA), and evaluation of the half-maximal inhibitory concentration (IC50) in constructed model. Finally, the entire samples were divided into three clusters based on model of necroptosis-associated lncRNAs to further compare immunotherapy in cold and hot tumors.ResultsA model was built up based on necroptosis-associated lncRNAs. The model revealed good consistence between calibration plots and prognostic prediction. The area of 1-, 3-, and 5-year OS under the ROC curve (AUC) were 0.707, 0.679, and 0.675. Risk groups could be helpful for systemic therapy due to the markedly diverse IC50 between risk groups. To our delight, clusters could effectively identify cold and hot tumors, which would be beneficial to accurate mediation. Clusters 2 and 3 were considered the hot tumor, which was more sensitive to immunotherapeutic drugs.ConclusionsThe outcomes of our study suggested that necroptosis-associated lncRNAs could effectively predict patients with BLCA prognosis, which may be helpful for distinguishing the cold and hot tumors and improving individual treatment of BLCA.
| S-EPMC9289196 | biostudies-literature
Project description:BackgroundIn the face of poor prognosis and immunotherapy failure of gastric cancer (GC), this project tried to find new potential biomarkers for predicting prognosis and precision medication to ameliorate the situation.MethodsTo form synthetic matrices, we retrieved stomach adenocarcinoma transcriptome data from Genotype-Tissue Expression Project (GTEx) and The Cancer Genome Atlas (TCGA). Necroptosis-related prognostic lncRNA was identified by coexpression analysis and univariate Cox regression. Then we performed the least absolute shrinkage and selection operator (LASSO) to construct the necroptosis-related lncRNA model. Next, the Kaplan-Meier analysis, time-dependent receiver operating characteristics (ROC), univariate Cox (uni-Cox) regression, multivariate Cox (multi-Cox) regression, nomogram, and calibration curves were made to verify and evaluate the model. Gene set enrichment analyses (GSEA), principal component analysis (PCA), immune analysis, and prediction of the half-maximal inhibitory concentration (IC50) in risk groups were also analyzed. For further discussing immunotherapy between the cold and hot tumors, we divided the entire set into two clusters based on necroptosis-related lncRNAs.ResultsWe constructed a model with 16 necroptosis-related lncRNAs. In the model, we found the calibration plots showed a good concordance with the prognosis prediction. The area's 1-, 2-, and 3-year OS under the ROC curve (AUC) were 0.726, 0.763, and 0.770, respectively. Risk groups could be a guide of systemic treatment because of significantly different IC50 between risk groups. Above all, clusters could help distinguish between the cold and hot tumors effectively and contribute to precise mediation. Cluster 2 was identified as the hot tumor and more susceptible to immunotherapeutic drugs.ConclusionThe results of this project supported that necroptosis-related lncRNAs could predict prognosis and help make a distinction between the cold and hot tumors for improving individual therapy in GC.
| S-EPMC8592775 | biostudies-literature