Coating with flexible DNA network enhanced T-cell activation and tumor killing for adoptive cell therapy.
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ABSTRACT:
SUBMITTER: Zhang Z
PROVIDER: S-EPMC8343197 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeCultured tumor fragments from melanoma metastases have been used for years as a source of tumor-infiltrating lymphocytes (TIL) for adoptive cell therapy (ACT). The expansion of tumor-reactive CD8(+) T cells with interleukin-2 (IL2) in these early cultures is critical in generating clinically active TIL infusion products, with a population of activated 4-1BB CD8(+) T cells recently found to constitute the majority of tumor-specific T cells.Experimental designWe used an agonistic anti-4-1BB antibody added during the initial tumor fragment cultures to provide in situ 4-1BB costimulation.ResultsWe found that addition of an agonistic anti-4-1BB antibody could activate 4-1BB signaling within early cultured tumor fragments and accelerated the rate of memory CD8(+) TIL outgrowth that were highly enriched for melanoma antigen specificity. This was associated with NFκB activation and the induction of T-cell survival and memory genes, as well as enhanced IL2 responsiveness, in the CD8(+) T cells in the fragments and emerging from the fragments. Early provision of 4-1BB costimulation also affected the dendritic cells (DC) by activating NFκB in DC and promoting their maturation inside the tumor fragments. Blocking HLA class I prevented the enhanced outgrowth of CD8(+) T cells with anti-4-1BB, suggesting that an ongoing HLA class I-mediated antigen presentation in early tumor fragment cultures plays a role in mediating tumor-specific CD8(+) TIL outgrowth.ConclusionsOur results highlight a previously unrecognized concept in TIL ACT that the tumor microenvironment can be dynamically regulated in the initial tumor fragment cultures to regulate the types of T cells expanded and their functional characteristics.
| S-EPMC4315752 | biostudies-literature
Project description:Tumor multidrug resistance (MDR) can result from overexpression of drug transporters and deregulation of cellular signaling transduction. New agents and strategies are required for overcoming MDR. Here, we report that tanshinone-1, a bioactive ingredient in traditional Chinese medicine, directly killed MDR tumor cells and their corresponding parental cells, which was potentiated by inhibition of secondary activation of signaling networks. Tanshinone-1 was slightly more potent at inducing cytotoxicity and apoptosis in MDR cells than in corresponding parental cells. Tanshinone-1-induced MDR cell killing was independent of the function and expression of drug transporters but was partially correlated with the phosphatase-dependent reduction of phospho-705-Stat3, which secondarily activated p38-, AKT-, and ERK-involved signaling networks. Cotreatments with p38, AKT, and ERK inhibitors potentiated the anti-MDR effects of tanshinone-1. Our study presents a model for MDR cell killing using a compound of natural origin. This model could lead to new therapeutic strategies for targeting signaling network(s) in MDR cancers as well as new strategies for multitarget design.
| S-EPMC3847321 | biostudies-literature
Project description:Optimal ex vivo expansion protocols of tumor-specific T cells followed by adoptive cell therapy must yield T cells able to home to tumors and effectively kill them. Our previous study demonstrated ex vivo activation in the presence of IL-12-induced optimal CD8+ T cell expansion and melanoma regression; however, adverse side effects, including autoimmunity, can occur. This may be due to transfer of high-avidity self-specific T cells. In this study, we compared mouse low- and high-avidity T cells targeting the tumor Ag tyrosinase-related protein 2 (TRP2). Not surprisingly, high-avidity T cells provide superior tumor control, yet low-avidity T cells can promote tumor regression. The addition of IL-12 during in vitro expansion boosts low-avidity T cell responsiveness, tumor regression, and prevents T cell exhaustion. In this study, we demonstrate that IL-12-primed T cells are resistant to PD-1/PD-L1-mediated suppression and retain effector function. Importantly, IL-12 preconditioning prevented exhaustion as LAG-3, PD-1, and TOX were decreased while simultaneously increasing KLRG1. Using intravital imaging, we also determined that high-avidity T cells have sustained contacts with intratumoral dendritic cells and tumor targets compared with low-avidity T cells. However, with Ag overexpression, this defect is overcome, and low-avidity T cells control tumor growth. Taken together, these data illustrate that low-avidity T cells can be therapeutically beneficial if cocultured with IL-12 cytokine during in vitro expansion and highly effective in vivo if Ag is not limiting. Clinically, low-avidity T cells provide a safer alternative to high-avidity, TCR-engineered T cells, as IL-12-primed, low-avidity T cells cause less autoimmune vitiligo.
| S-EPMC8293279 | biostudies-literature
Project description:Although T cell-recruiting CD3-binding bispecific antibodies (BiMAb) have been proven to be clinically effective for hematologic malignancies, the success of BiMAb targeting solid tumor-associated antigens (TAA) in carcinomas so far remains poor. We reasoned that provision of co-stimulatory BiMAb in combination with αTAA-αCD3 BiMAb would boost T cell activation and proliferative capacity, and thereby facilitate the targeting of weakly or heterogeneously expressed tumor antigens. Various αTAA-αCD3 and αTAA-αCD28 BiMAb in a tetravalent IgG1-Fc based format have been analyzed, targeting multiple breast cancer antigens including HER2, EGFR, CEA, and EpCAM. Moreover, bifunctional fusion proteins of αTAA-tumor necrosis factor ligand (TNFL) superfamily members including 4-1BBL, OX40L, CD70 and TL1A have been tested. The functional activity of BiMAb was assessed using co-cultures of tumor cell lines and purified T cells in monolayer and tumor spheroid models. Only in the presence of tumor cells, αTAA-αCD3 BiMAb activated T cells and induced cytotoxicity in vitro, indicating a strict dependence on cross-linking. Combination treatment of αTAA-αCD3 BiMAb and co-stimulatory αTAA-αCD28 or αTAA-TNFL fusion proteins drastically enhanced T cell activation in terms of proliferation, activation marker expression, cytokine secretion and tumor cytotoxicity. Furthermore, BiMAb providing co-stimulation were shown to reduce the minimally required dose to achieve T cell activation by at least tenfold. Immuno-suppressive effects of TGF-β and IL-10 on T cell activation and memory cell formation could be overcome by co-stimulation. BiMAb-mediated co-stimulation was further augmented by immune checkpoint-inhibiting antibodies. Effective co-stimulation could be achieved by targeting a second breast cancer antigen, or by targeting fibroblast activation protein (FAP) expressed on another target cell. In tumor spheroids derived from pleural effusions of breast cancer patients, co-stimulatory BiMAb were essential for the activation tumor-infiltrating lymphocytes and cytotoxic anti-tumor responses against breast cancer cells. Taken together we showed that co-stimulation significantly potentiated the tumoricidal activity of T cell-activating BiMAb while preserving the dependence on TAA recognition. This approach could provide for a more localized activation of the immune system with higher efficacy and reduced peripheral toxicities.
| S-EPMC8415424 | biostudies-literature
Project description:Recent studies show that tumor cells are vulnerable to mechanical stresses and undergo calcium-dependent apoptosis (mechanoptosis) with mechanical perturbation by low-frequency ultrasound alone. To determine if tumor cells are particularly sensitive to mechanical stress in certain phases of the cell cycle, inhibitors of the cell-cycle phases are tested for effects on mechanoptosis. Most inhibitors show no significant effect, but inhibitors of mitosis that cause microtubule depolymerization increase the mechanoptosis. Surprisingly, ultrasound treatment also disrupts microtubules independent of inhibitors in tumor cells but not in normal cells. Ultrasound causes calcium entry through mechanosensitive Piezo1 channels that disrupts microtubules via calpain protease activation. Myosin IIA contractility is required for ultrasound-mediated mechanoptosis and microtubule disruption enhances myosin IIA contractility through activation of GEF-H1 and RhoA pathway. Further, ultrasound promotes contractility-dependent Piezo1 expression and localization to the peripheral adhesions where activated Piezo1 allows calcium entry to continue feedback loop. Thus, the synergistic action of ultrasound and nanomolar concentrations of microtubule depolymerizing agents can enhance tumor therapies.
| S-EPMC8459596 | biostudies-literature
Project description:The manipulation of T cell metabolism to enhance anti-tumor activity is an area of active investigation. Here, we report that activating the amino acid starvation response in effector CD8+ T cells ex vivo using the general control non-depressible 2 (GCN2) agonist halofuginone (halo) enhances oxidative metabolism and effector function. Mechanistically, we identified autophagy coupled with the CD98-mTOR axis as key downstream mediators of the phenotype induced by halo treatment. The adoptive transfer of halo-treated CD8+ T cells into tumor-bearing mice led to robust tumor control and curative responses. Halo-treated T cells synergized in vivo with a 4-1BB agonistic antibody to control tumor growth in a mouse model resistant to immunotherapy. Importantly, treatment of human CD8+ T cells with halo resulted in similar metabolic and functional reprogramming. These findings demonstrate that activating the amino acid starvation response with the GCN2 agonist halo can enhance T cell metabolism and anti-tumor activity.
| S-EPMC10983112 | biostudies-literature
Project description:Cervical cancer is one of the most common malignancies among females. As a virus-related cancer, cervical cancer has attracted a lot of attention to develop virus-targeted immune therapy, including vaccine and adoptive immune cell therapy (ACT). Adoptive tumor infiltrating lymphocytes (TILs) cell therapy has been found to be able to control advanced disease progression in some cervical cancer patients who have received several lines of treatment in a pilot clinical trial. In addition, sustainable therapeutic effect has been identified in some cases. The safety risks of TIL therapy for patients are minimal or at least manageable. In this review, we focused on the versatility of TILs and tried to summarize potential strategies to improve the therapeutic effect of TILs and discuss related perspectives.
| S-EPMC9897649 | biostudies-literature
Project description:The manipulation of T cell metabolism to enhance anti-tumor activity is an area of active investigation. Here, we report that activating the amino acid starvation response in effector CD8+ T cells ex vivo using the General Control Non-depressible 2 (GCN2) agonist halofuginone (halo) enhances oxidative metabolism and effector function. Further characterization revealed that halo-treated CD8+ T cells increased expression of the large neutral amino acid (LNAA) transporter CD98 as well as the co-stimulatory marker 4-1BB. Mechanistically, we identified autophagy coupled with the CD98-mTOR axis as key downstream mediators of the phenotype induced by halo treatment. The adoptive transfer of halo-treated CD8+ T cells into mice bearing well-established tumors led to robust tumor control and curative responses. Halo-treated T cells also synergized in vivo with a 4-1BB agonistic antibody to control tumor growth in a mouse model resistant to immunotherapy. Importantly, treatment of human CD8+ T cells with halo resulted in similar metabolic and functional reprogramming. These findings demonstrate that activating the amino acid starvation response with the GCN2 agonist halofuginone can enhance T cell metabolism, effector function and anti-tumor activity, with the potential to augment existing clinical immunotherapeutic approaches.
2024-02-17 | GSE255244 | GEO
Project description:The potency of immunotherapies targeting endogenous tumor antigens is hindered by immune tolerance. We created a therapeutic agent comprised of a tumor-homing module fused to a functional domain capable of selectively rendering tumor cells sensitive to foreign antigen-specific CD8(+) T cell-mediated immune attack, and thereby, circumventing concerns for immune tolerance. The tumor-homing module is comprised of a single-chain variable fragment (scFv) that specifically binds to mesothelin (Meso), which is commonly overexpressed in human cancers, including ovarian tumors. The functional domain is comprised of the Fc portion of IgG2a protein and foreign immunogenic CD8(+) T cell epitope flanked by furin cleavage sites (R), which can be recognized and cleaved by furin that is highly expressed in the tumor microenvironment. We show that our therapeutic protein specifically loaded antigenic epitope onto the surface of mesothelin-expressing tumor cells, rendering tumors susceptible to antigen-specific cytotoxic CD8(+) T lymphocytes (CTL)-mediated killing in vitro and in vivo. Our findings have important implications for bypassing immune tolerance to enhance cancer immunotherapy.
| S-EPMC3589158 | biostudies-literature
Project description:Adoptive cell transfer therapy for cancer has existed for decades and is experiencing a resurgence in popularity that has been facilitated by improved methods of production, techniques for genetic modification, and host preconditioning. The trafficking of adoptively transferred lymphocytes and infiltration into the tumor microenvironment is sine qua non for successful tumor eradication; however, the paradox of extremely poor trafficking of lymphocytes into the tumor microenvironment raises the issue of how best to deliver these cells to optimize entry into tumor tissue. We examined the route of administration as a potential modifier of both trafficking and antitumor efficacy. Femoral artery cannulation and tail vein injection for the intra-arterial (IA) and IV delivery, respectively, were utilized in the B16-OVA/OT-I mouse model system. Both IV and IA infusions showed decreased tumor growth and prolonged survival. However, although significantly increased T-cell tumor infiltration was observed in IA mice, tumor growth and survival were not improved as compared with IV mice. These studies suggest that IA administration produces increased early lymphocyte trafficking, but a discernable survival benefit was not seen in the murine model examined.
| S-EPMC6092084 | biostudies-other