Browse
Submit Data
Databases
API
Help

Dataset Information

10 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Pre-conditioning modifies the TME to enhance solid tumor CAR T cell efficacy and endogenous protective immunity.

ABSTRACT: Chimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its effectiveness in patients with solid tumors has been limited. While CAR T cells for the treatment of advanced prostate and pancreas cancer, including those targeting prostate stem cell antigen (PSCA), are being clinically evaluated and are anticipated to show bioactivity, their safety and the impact of the immunosuppressive tumor microenvironment (TME) have not been faithfully explored preclinically. Using a novel human PSCA knockin (hPSCA-KI) immunocompetent mouse model, we evaluated the safety and therapeutic efficacy of PSCA-CAR T cells. We demonstrated that cyclophosphamide (Cy) pre-conditioning significantly modified the immunosuppressive TME and was required to uncover the efficacy of PSCA-CAR T cells in metastatic prostate and pancreas cancer models, with no observed toxicities in normal tissues with endogenous expression of PSCA. This combination dampened the immunosuppressive TME, generated pro-inflammatory myeloid and T cell signatures in tumors, and enhanced the recruitment of antigen-presenting cells, as well as endogenous and adoptively transferred T cells, resulting in long-term anti-tumor immunity.

SUBMITTER: Murad JP

PROVIDER: S-EPMC8261088 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Impact of cyclophosphamide pre-conditioning on solid tumor microenvironemt and impacts on CAR T cell therapy

Project description:Tumor bearing mice treated with or without cyclophosphamide (100mg/kg; i.p.) and mock T cells or CAR T cells. Tumors harvested at early timepoint following therapy and RNA extracted from whole tumors was used for bulk RNA sequencing analysis.

2021-01-21 | GSE165197 | GEO

Target selection of CAR T cell therapy in accordance with the TME for solid tumors.

Project description:Chimeric antigen receptor-engineered T (CAR T) cell therapy has made great progress in hematological malignancies and resulted in two newly FDA-approved drugs specific for CD19, Kymriah and Yescarta. To some extent, this success is attributable to the appropriately selected antigen, CD19, a cell surface protein that is uniformly and strongly expressed on malignant B cells. This result indicates that a proper CAR target is of great importance to the success of this technique. Another key factor contributing to the success of hematological malignancies can be ascribed to the nonphysical tumor microenvironment (TME). The TME in solid tumors is complicated and has a specific niche favorable for tumor progression with physical barriers, multiple mechanisms of immunosuppression, and a variety of biochemical factors, thus resulting in limited efficacy of CAR T cell therapy in clinical trials with cancer patients. Therefore, the inhospitable solid TME becomes a major hurdle in translating the success of CAR T cell therapy in hematological malignancies to solid tumors. Here, we provide our perspective on how to improve the success of CAR T therapy in solid tumors by focusing on the aspects of target selection and the related TME in CAR T cell design, especially stressing the interplay between them. With four kinds of antigenic CAR targets as examples in this review, we anticipate that the overall consideration of both factors will further expand CAR T cell therapy in clinical trials.

| S-EPMC6405971 | biostudies-literature

Synthetic ROR?t Agonists Enhance Protective Immunity.

Project description:The T cell specific ROR? isoform ROR?t has been shown to be the key lineage-defining transcription factor to initiate the differentiation program of TH17 and TC17 cells, cells that have demonstrated antitumor efficacy. ROR?t controls gene networks that enhance immunity including increased IL17 production and decreased immune suppression. Both synthetic and putative endogenous agonists of ROR?t have been shown to increase the basal activity of ROR?t enhancing TH17 cell proliferation. Here, we show that activation of ROR?t using synthetic agonists drives proliferation of TH17 cells while decreasing levels of the immune checkpoint protein PD-1, a mechanism that should enhance antitumor immunity while blunting tumor associated adaptive immune resistance. Interestingly, putative endogenous agonists drive proliferation of TH17 cells but do not repress PD-1. These findings suggest that synthetic agonists of ROR?t should activate TC17/TH17 cells (with concomitant reduction in the Tregs population), repress PD-1, and produce IL17 in situ (a factor associated with good prognosis in cancer). Enhanced immunity and blockage of immune checkpoints has transformed cancer treatment; thus such a molecule would provide a unique approach for the treatment of cancer.

| S-EPMC5178133 | biostudies-literature

Pre-conditioning induces the precocious differentiation of neonatal astrocytes to enhance their neuroprotective properties.

Project description:Hypoxic preconditioning reprogrammes the brain's response to subsequent H/I (hypoxia-ischaemia) injury by enhancing neuroprotective mechanisms. Given that astrocytes normally support neuronal survival and function, the purpose of the present study was to test the hypothesis that a hypoxic preconditioning stimulus would activate an adaptive astrocytic response. We analysed several functional parameters 24 h after exposing rat pups to 3 h of systemic hypoxia (8% O2). Hypoxia increased neocortical astrocyte maturation as evidenced by the loss of GFAP (glial fibrillary acidic protein)-positive cells with radial morphologies and the acquisition of multipolar GFAP-positive cells. Interestingly, many of these astrocytes had nuclear S100B. Accompanying their differentiation, there was increased expression of GFAP, GS (glutamine synthetase), EAAT-1 (excitatory amino acid transporter-1; also known as GLAST), MCT-1 (monocarboxylate transporter-1) and ceruloplasmin. A subsequent H/I insult did not result in any further astrocyte activation. Some responses were cell autonomous, as levels of GS and MCT-1 increased subsequent to hypoxia in cultured forebrain astrocytes. In contrast, the expression of GFAP, GLAST and ceruloplasmin remained unaltered. Additional experiments utilized astrocytes exposed to exogenous dbcAMP (dibutyryl-cAMP), which mimicked several aspects of the preconditioning response, to determine whether activated astrocytes could protect neurons from subsequent excitotoxic injury. dbcAMP treatment increased GS and glutamate transporter expression and function, and as hypothesized, protected neurons from glutamate excitotoxicity. Taken altogether, these results indicate that a preconditioning stimulus causes the precocious differentiation of astrocytes and increases the acquisition of multiple astrocytic functions that will contribute to the neuroprotection conferred by a sublethal preconditioning stress.

| S-EPMC3153963 | biostudies-literature

Genetic Modification Strategies to Enhance CAR T Cell Persistence for Patients With Solid Tumors.

Project description:Immunotherapy with chimeric antigen receptor (CAR) T cells offers a promising method to improve cure rates and decrease morbidities for patients with cancer. In this regard, CD19-specific CAR T cell therapies have achieved dramatic objective responses for a high percent of patients with CD19-positive leukemia or lymphoma. Most patients with solid tumors however, have experienced transient or no benefit from CAR T cell therapies. Novel strategies are therefore needed to improve CAR T cell function for patients with solid tumors. One obstacle for the field is limited CAR T cell persistence after infusion into patients. In this review we highlight genetic engineering strategies to improve CAR T cell persistence for enhancing antitumor activity for patients with solid tumors.

| S-EPMC6384227 | biostudies-literature

Regional CAR T cell therapy: An ignition key for systemic immunity in solid tumors.

Project description:The success of chimeric antigen receptor (CAR) T cell therapy in solid tumors, unlike in hematologic malignancies, is limited by inadequate tumor infiltration and T cell dysfunction and exhaustion. Regional delivery of CAR T cells in patients with solid tumors is safe and feasible; promotes infiltration, proliferation, and trafficking; and ignites functionally persisting systemic immunity.

| S-EPMC9197990 | biostudies-literature

Genetic Modification of Cytokine Signaling to Enhance Efficacy of CAR T Cell Therapy in Solid Tumors

Project description:Chimeric antigen receptor (CAR) T cell therapy has shown unprecedented success in treating advanced hematological malignancies. Its effectiveness in solid tumors has been limited due to heterogeneous antigen expression, a suppressive tumor microenvironment, suboptimal trafficking to the tumor site and poor CAR T cell persistence. Several approaches have been developed to overcome these obstacles through various strategies including the genetic engineering of CAR T cells to blunt the signaling of immune inhibitory receptors as well as to modulate signaling of cytokine/chemokine molecules and their receptors. In this review we offer our perspective on how genetically modifying cytokine/chemokine molecules and their receptors can improve CAR T cell qualities such as functionality, persistence (e.g. resistance to pro-apoptotic signals) and infiltration into tumor sites. Understanding how such modifications can overcome barriers to CAR T cell effectiveness will undoubtedly enhance the potential of CAR T cells against solid tumors.

| S-EPMC8552010 | biostudies-literature

Endogenous cathelicidin production limits inflammation and protective immunity to Mycobacterium avium in mice.

Project description:The production of antimicrobial peptides, such as the cathelicidins, plays a prominent role in the innate immune response against microbial pathogens. Cathelicidins are widely distributed amongst living organisms, and the antimicrobial peptides generated by proteolysis of the precursor forms are typically cationic and ?-helical, a structure that facilitates their interaction and insertion into anionic bacterial cell walls and membranes, causing damage and promoting microbial death. Here, we found that mouse cathelicidin (Camp) expression was induced in bone marrow-derived macrophages by infection with Mycobacterium avium in a TLR2- and TNF-dependent manner. However, the endogenous production of the cathelin-related antimicrobial peptide (CRAMP) was not required for the bacteriostasis of M. avium either in primary cultures of macrophages or in vivo, as shown by the use of CRAMP-null mice. In contrast, the lack of Camp led to a transient improvement of M. avium growth control in the spleens of infected mice while at the same time causing an exacerbation of the inflammatory response to infection. Our data highlight the anti-inflammatory effects of CRAMP and suggests that virulent mycobacteria may possess strategies to escape its antimicrobial activity.

| S-EPMC4220664 | biostudies-literature

Innate immunity limits protective adaptive immune responses against pre-erythrocytic malaria parasites.

Project description:Immunization with attenuated whole Plasmodium sporozoites constitutes a promising vaccination strategy. Compared to replication-deficient parasites, immunization with replication-competent parasites confers better protection and also induces a type I IFN (IFN-1) response, but whether this IFN-1 response has beneficial or adverse effects on vaccine-induced adaptive immunity is not known. Here, we show that IFN-1 signaling-deficient mice immunized with replication-competent sporozoites exhibit superior protection against infection. This correlates with superior CD8 T cell memory including reduced expression of the exhaustion markers PD-1 and LAG-3 on these cells and increased numbers of memory CD8 T cells in the liver. Moreover, the adoptive transfer of memory CD8 T cells from the livers of previously immunized IFN-1 signaling-deficient mice confers greater protection against liver stage parasites. However, the detrimental role of IFN-1 signaling is not CD8 T cell intrinsic. Together, our data demonstrate that liver stage-engendered IFN-1 signaling impairs hepatic CD8 T cell memory via a CD8 T cell-extrinsic mechanism.

| S-EPMC6718385 | biostudies-literature

PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR-T cell efficacy in solid tumours

Project description:Although adoptive T cell therapy has shown remarkable clinical efficacy in hematological malignancies, its success in combating solid tumours has been limited. Here we report that PTPN2 deletion in T cells enhances cancer immunosurveillance and the efficacy of adoptively transferred tumour-specific T cells. T cell-specific PTPN2 deficiency prevented tumours forming in aged mice heterozygous for the tumour suppressor p53. Adoptive transfer of PTPN2-deficient CD8+ T cells markedly repressed tumour formation in mice bearing mammary tumours. Moreover, PTPN2 deletion in T cells expressing a chimeric antigen receptor (CAR) specific for the oncoprotein HER-2 increased the activation of the Src family kinase LCK and cytokine-induced STAT-5 signalling, thereby enhancing both CAR-T cell activation and homing to CXCL9/10 expressing tumours to eradicate HER-2+ mammary tumours in vivo. Our findings define PTPN2 as a target for bolstering T-cell mediated anti-tumour immunity and CAR-T cell therapy against solid tumours.

| S-SCDT-EMBOJ-2019-103637 | biostudies-other

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data