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Personalized dendritic cell vaccine facilitates the preparation of neoantigen-reactive T cells for adoptive transfer (scTCR-Seq)

ABSTRACT: Adoptive cell transfer (ACT) using neoantigen-specific T cells is an effective immunotherapeutic strategy. However, the difficulty in identifying and screening neoantigen-specific T cells limits its widespread application. Here, we prepared neoantigen-reactive T cells (NRTs) after immunization with a tumor lysate-loaded dendritic cell (DC) vaccine (OCDC) for ACT. Our results demonstrated that the OCDC vaccine could induce a neoantigen-specific immune response, and it was feasible to prepare NRTs by loading immunogenic neoantigens onto DCs and coculturing them with spleen lymphocytes from mice immunized with the OCDC vaccine. We then transferred these NRTs back to the LL/2 tumor-bearing mice after OCDC vaccine immunization and found that OCDC vaccine and NRTs adoptive transfer combination treatment could induce a stronger antitumor response. Furthermore, we found that infused NRTs could migrate into the tumor microenvironment to exert antitumor effects. Our research provides a new and convenient method of preparing NRTs for ACT. The clinical translation of this approach has the potential to increase ACT efficacy.

ORGANISM(S): Mus musculus

PROVIDER: GSE271086 | GEO | 2024/07/05

REPOSITORIES: GEO

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Personalized dendritic cell vaccine facilitates the preparation of neoantigen-reactive T cells for adoptive transfer (scRNA-Seq)

Project description:Adoptive cell transfer (ACT) using neoantigen-specific T cells is an effective immunotherapeutic strategy. However, the difficulty in identifying and screening neoantigen-specific T cells limits its widespread application. Here, we prepared neoantigen-reactive T cells (NRTs) after immunization with a tumor lysate-loaded dendritic cell (DC) vaccine (OCDC) for ACT. Our results demonstrated that the OCDC vaccine could induce a neoantigen-specific immune response, and it was feasible to prepare NRTs by loading immunogenic neoantigens onto DCs and coculturing them with spleen lymphocytes from mice immunized with the OCDC vaccine. We then transferred these NRTs back to the LL/2 tumor-bearing mice after OCDC vaccine immunization and found that OCDC vaccine and NRTs adoptive transfer combination treatment could induce a stronger antitumor response. Furthermore, we found that infused NRTs could migrate into the tumor microenvironment to exert antitumor effects. Our research provides a new and convenient method of preparing NRTs for ACT. The clinical translation of this approach has the potential to increase ACT efficacy.

2024-07-05 | GSE271085 | GEO

Personalized dendritic cell vaccine facilitates the preparation of neoantigen-reactive T cells for adoptive transfer (scTCR-Seq)

Project description:Personalized dendritic cell vaccine facilitates the preparation of neoantigen-reactive T cells for adoptive transfer (scTCR-Seq)

| PRJNA1129586 | ENA

Improved expansion, functionality and tumor targeting of adoptively transferred T cells with kinetically engineered IL-2

Project description:The adoptive transfer of cancer-specific T cells in combination with high dose interleukin-2 (IL-2) is able to induce effective anti-tumor responses. However, tumors frequently relapse after an initial response and the known toxicities of IL-2 further limit the use of this therapy. NKTR-214 is a CD122-biased polyethylene glycol (PEG)-genetically engineered IL-2 designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβγ) to preferentially activate and expand CD8 T and natural killer (NK) cells over T regulatory cells (Tregs) in the tumor. We report that combination of adoptive T cell transfer (ACT) and NKTR-214 markedly increases the proliferation, homing and polyfunctionality of antitumor T cells into the tumor. The treatment is well tolerated and leads to robust anti-tumor response in the aggressive B16F10 model. These results suggest that NKTR-214 could improve the efficacy of ACT protocols tested in humans.

2019-08-07 | GSE118748 | GEO

Inhibition of Akt promotes immunologic memory in tumor-infiltrating lymphocytes isolated from patients with melanoma

Project description:Adoptive cell immunotherapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) can result in complete regression of advanced melanoma in some patients, but the efficacy of this potentially curative therapy is limited by poor persistence of TIL after adoptive-transfer. Pharmacologic inhibition of the serine/threonine kinase Akt has recently been shown to promote immunologic memory in viral-specific murine models, but whether this approach may enhance features of memory (e.g. long-term persistence) in TIL which are characteristically exhausted and senescent is not established. Here we show that pharmacologic inhibition of Akt enables expansion of TIL with the transcriptional, metabolic and functional properties characteristic of memory T cells. Consequently, Akt inhibition results in enhanced persistence of TIL after adoptive transfer into an immunodeficient animal model and augments antitumor immunity of CD8 T cells in a mouse model of cell-based immunotherapy for melanoma. Pharmacologic inhibition of Akt represents a novel immunometabolomic approach to enhance the persistence of anti-tumor T cells and improve the efficacy of cellbased immunotherapy for metastatic cancer.

2015-06-03 | GSE60977 | GEO

Neoantigen-Augmented iPSC-based Cancer Vaccine Combined with Local Radiotherapy Promotes Systemic Antitumor Immunity in Poorly Immunogenic Cancers

Project description:Although irradiated induced-pluripotent stem cells (iPSCs) as a prophylactic cancer vaccine elicit an antitumor immune response, the therapeutic efficacy of iPSC-based cancer vaccines is not promising due to their insufficient antigenicity and the immunosuppressive tumor microenvironment. Here, we found that neoantigen-engineered iPSC cancer vaccines can trigger neoantigen-specific T cell responses to eradicate cancer cells and increase the therapeutic efficacy of RT in poorly immunogenic colorectal cancer (CRC) and triple-negative breast cancer (TNBC). We generated neoantigen-augmented iPSCs (NA-iPSCs) by engineering AAV2 vector carrying murine neoantigens and evaluated their therapeutic efficacy in combination with radiotherapy. After administration of NA-iPSC cancer vaccine and radiotherapy, we found that ~60% of tumor-bearing mice achieved a complete response in microsatellite-stable CRC model. Furthermore, splenocytes from mice treated with NA-iPSC plus RT produced high levels of IFN secretion in response to neoantigens and had a greater cytotoxicity to cancer cells, suggesting that the NA-iPSC vaccine combined with radiotherapy elicited a superior neoantigen-specific T-cell response to eradicate cancer cells. The superior therapeutic efficacy of NA-iPSCs engineered by mouse TNBC neoantigens was also observed in the syngeneic immunocompetent TNBC mouse model. We found that the risk of spontaneous lung and liver metastasis was dramatically decreased by NA-iPSCs plus RT in the TNBC animal model. Altogether, these results indicated that autologous iPSC cancer vaccines engineered by neoantigens can elicit a high neoantigen-specific T-cell response, promote tumor regression and reduce the risk of distant metastasis in combination with local radiotherapy.

2024-04-03 | GSE262852 | GEO

A Temporal Switch in the Germinal Center Determines Differential Output of Memory B and Plasma Cells

Project description:There is little insight into or agreement about the signals that control differentiation of memory B cells (MBC) and long-lived plasma cells (LLPC). By performing BrdU pulse-labeling studies, we found that MBC formation preceded the formation of LLPC in an adoptive transfer immunization system, which allowed for a synchronized Ag-specific response with homogeneous Ag-receptor, yet at natural precursor frequencies. We confirmed observations in wild type (WT) mice and extended them with germinal center (GC) disruption experiments and variable region gene sequencing. We thus show that the GC response undergo a temporal switch in its output as it matures, revealing that the reaction engenders both MBC subsets with different immune effector function and, ultimately, LLPC at largely separate points in time. These data demonstrate the kinetics of the formation of the cells that provide stable humoral immunity and therefore have implications for autoimmunity, vaccine development, and for understanding long-term pathogen resistance. Adoptive transfer of B1-8i+/- genetically targeted BALB/cJ mice B cells into AM14 Transgenic (Tg) x VÎº8R genetically targeted BALB/cJ mice. Naive, memory, early and late GC B cells.

2016-01-05 | E-GEOD-76502 | biostudies-arrayexpress

Tumor-reactive T cell clonotype dynamics underlying clinical response to TIL therapy in melanoma [scTCR-seq]

Project description:Adoptive cell therapy (ACT) using in vitro expanded tumor-infiltrating lymphocytes (TILs) has inconsistent clinical responses. To better understand determinants of therapeutic success, we tracked TIL clonotypes from baseline tumors to ACT products and post-ACT blood and tumor samples in melanoma patients using single-cell RNA and T cell receptor (TCR) sequencing. Patients with clinical responses had baseline tumors enriched in tumor-reactive TILs, and these were more effectively mobilized upon in vitro expansion, yielding products enriched in tumor-specific CD8+ cells that preferentially infiltrated tumors post-ACT. Conversely, lack of clinical responses was associated with tumors devoid of tumor-reactive resident clonotypes and with cell products mostly composed of blood-borne clonotypes that persisted in blood but not in tumors post-ACT. Upon expansion, tumor-specific TILs lost tumor-associated transcriptional signatures, including exhaustion, and responders exhibited an intermediate exhausted effector state after TIL engraftment in the tumor, suggesting functional reinvigoration. Our findings provide insight into the nature and dynamics of tumor-specific clonotypes associated with clinical response to TIL-ACT, with implications for treatment optimization.

2023-08-01 | GSE229860 | GEO

CD4 T cell activating neoantigens enhance personalized cancer vaccine efficacy

Project description:Personalized cancer vaccines aim to activate and expand cytotoxic anti-tumor CD8+ T cells to recognize and kill tumor cells. However, the role of CD4+ T cell activation in the clinical benefit of these vaccines is not well defined. We previously established a personalized neoantigen vaccine (PancVAX) for the pancreatic cancer cell line Panc02, which activates tumor-specific CD8+ T cells but required combinatorial checkpoint modulators to achieve therapeutic efficacy. To determine the effects of neoantigen-specific CD4+ T cell activation, we generated a new vaccine (PancVAX2) targeting both MHCI- and MHCII-specific neoantigens. Tumor-bearing mice vaccinated with PancVAX2 had significantly improved control of tumor growth and long-term survival benefit without concurrent administration of checkpoint inhibitors. PancVAX2 significantly enhanced priming and recruitment of neoantigen-specific CD8+ T into the tumor with lower PD1 expression after reactivation compared to the CD8+ vaccine alone. Vaccine-induced neoantigen- specific Th1 CD4+ T cells in the tumor were associated with decreased T regulatory cells (Tregs). Consistent with this, PancVAX2 was associated with more pro-immune myeloid-derived suppressor cells and M1-like macrophages in the tumor demonstrating a less immunosuppressive tumor microenvironment. This study demonstrates the biological importance of prioritizing and including CD4 T cell-specific neoantigens for personalized cancer vaccine modalities.

2023-12-11 | GSE244992 | GEO

Personalized dendritic cell vaccine facilitates the preparation of neoantigen-reactive T cells for adoptive transfer (scRNA-Seq)

Project description:Personalized dendritic cell vaccine facilitates the preparation of neoantigen-reactive T cells for adoptive transfer (scRNA-Seq)

| PRJNA1129585 | ENA

Thioredoxin-1 Alters Anti-Tumor T Cell Immuno-Metabolic Phenotype

Project description:ABSTRACT Adoptive transfer of tumor epitope reactive T cells is a promising strategy to control tumor growth. However, chronically stimulated T cells expanded for adoptive cell transfer (ACT) are susceptible to cells death in an oxidative tumor microenvironment. Since oxidation of cell surface thiols (c-SH) also alters functionality of proteins, we hypothesized that increased level of thioredoxin, an anti-oxidant molecule that facilitates reduction of proteins by cysteine thioldisulfide exchange, in T cells will result in sustained anti-tumor function. Using Pmel-Trx1 transgenic mouse derived splenic T cells we observed higher c-SH expression that inversely correlated with ROS, and susceptibility to TCR restimulation or oxidation mediated cell death. These Trx1 overexpressing T cells showed CD62Lhi central memory-like (Tcm) phenotype with reduced glucose uptake (2-NBDGlo) and effector function (IFNγlo). Further, using tumor reactive T cells cultured in presence of recombinant Trx resulted in increased dependence of T cells on mitochondrial metabolism and led to improved tumor control. Thus, strategies to increase antioxidant capacity of anti-tumor T cells modulate its immune-metabolic phenotype leading to improved immunotherapeutic control of established tumors.

2021-12-20 | E-MTAB-7571 | biostudies-arrayexpress

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