mRNAs encoding IL-12 and a decoy-resistant variant of IL-18 synergize to engineer T cells for efficacious intratumoral adoptive immunotherapy

Olivera, Irene; Bolaños, Elixabet; González-Gomariz, José; Hervás-Stubbs, Sandra; Mariño, Karina; Luri-Rey, Carlos; Etxeberría, Iñaki; Cirella, Assunta; Egea, Josune; Glez-Vaz, Javier; Garasa, Saray; Eguren-Santamaría, Iñaki; Guedan, Sonia; Sanmamed, Miguel F.; Berraondo, Pedro; Rabinovich, Gabriel A.; Teijeira, Álvaro; Melero, Ignacio

doi:10.1016/j.xcrm.2023.100978

Cited by 15 publications

(6 citation statements)

References 90 publications

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“…T cells that are reactive against tumor antigens are found in patients with cancer and can selectively eliminate tumor cells (26). Over the last few decades, tumor antigens have been targets of immunotherapy, including adoptive T-cell therapies (27)(28)(29). Although the outcomes in hematological malignancies and melanoma are encouraging, successful treatments targeting selfantigens in solid tumors are limited (30,31).…”

Section: Discussionmentioning

confidence: 99%

Tumor-associated CD8+T cell tolerance induced by erythroid progenitor cells

Fan,

Peng,

Wang

et al. 2024

Front. Immunol.

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IntroductionCD8+T cell tolerance plays an important role in tumor escape. Recent studies have shown that CD45+ erythroid progenitor cells (CD45+EPCs) generated through splenic extramedullary erythropoiesis suppress tumor immunity. However, the mechanism underlying how CD45+EPCs mediate CD8+T cell tolerance remains incompletely understood and requires further research.MethodsIn this study, the antigen-processing abilities of CD45+EPCs was verified through both in vitro and in vivo experiments. We have used the method of co-culture in vitro and adoptive transfer experiments in vivo to explore the effects of CD45+EPCs on CD8+T cell tolerance. RNA-sequencing analysis and blocking experiments were used to evaluate the role of ROS in the CD45+EPC mediated tolerance of CD8+T cells. Finally, we incorporated uric acid into the adoptive transfer experiments to rescue the CD45+EPC mediated tumor-promoting effect.Results and discussionWe found that CD45+EPCs take up soluble proteins, present antigenic epitopes on their surface, and induce antigen-specific CD8+T cell anergy. In addition, we found that CD45+EPC directly nitrates tyrosine within the TCR/CD8 complex via the production of reactive oxygen species and peroxynitrite, preventing CD8+ T cells from responding to their specific peptide antigens. Furthermore, uric acid treatment effectively abolished the immunosuppressive effects of CD45+EPCs during CD8+T cell adoptive transfer, thereby enhancing the anti-tumor efficacy. These results demonstrated that CD8+T cell tolerance in tumor-bearing mice is induced by CD45+EPCs. The results of this study have direct implications for tumor immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Tumor-associated CD8+T cell tolerance induced by erythroid progenitor cells

Fan,

Peng,

Wang

et al. 2024

Front. Immunol.

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“…As a result, DR-18 not only maintained signaling potential but also exerted a robust antitumor activity by expanding the pool of stem-like TCF1 + precursor CD8(+) memory T cells and decreasing T cell exhaustion [ 145 ]. In addition, pre-stimulation with the combination of IL-12 and IL-18 contributes to memory T cells proliferation [ 146 ], and engineering T cells with scIL-12 and DR-18 demonstrates potent antitumoral effects [ 147 ]. Subsequently, membrane-bound form of IL-12 (mbIL12) engineered T cells were designed to improves potency of CAR-T cells both in vitro and in vivo [ 148 ].…”

Section: Other Cytokines and Signalings That Regulate T Cell Fate And...mentioning

confidence: 99%

New insights into the stemness of adoptively transferred T cells by γc family cytokines

Luo,

Gong,

Zhang

et al. 2023

Cell Commun Signal

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T cell-based adoptive cell therapy (ACT) has exhibited excellent antitumoral efficacy exemplified by the clinical breakthrough of chimeric antigen receptor therapy (CAR-T) in hematologic malignancies. It relies on the pool of functional T cells to retain the developmental potential to serially kill targeted cells. However, failure in the continuous supply and persistence of functional T cells has been recognized as a critical barrier to sustainable responses. Conferring stemness on infused T cells, yielding stem cell-like memory T cells (TSCM) characterized by constant self-renewal and multilineage differentiation similar to pluripotent stem cells, is indeed necessary and promising for enhancing T cell function and sustaining antitumor immunity. Therefore, it is crucial to identify TSCM cell induction regulators and acquire more TSCM cells as resource cells during production and after infusion to improve antitumoral efficacy. Recently, four common cytokine receptor γ chain (γc) family cytokines, encompassing interleukin-2 (IL-2), IL-7, IL-15, and IL-21, have been widely used in the development of long-lived adoptively transferred TSCM in vitro. However, challenges, including their non-specific toxicities and off-target effects, have led to substantial efforts for the development of engineered versions to unleash their full potential in the induction and maintenance of T cell stemness in ACT. In this review, we summarize the roles of the four γc family cytokines in the orchestration of adoptively transferred T cell stemness, introduce their engineered versions that modulate TSCM cell formation and demonstrate the potential of their various combinations.

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“…Spatial and temporal heterogeneity in tumor antigen expression, as well as obstacles to infiltrating tumor masses protected from immunologic cell kill through abnormal vasculature and a hostile TME are the major factors that pose barriers to an efficacious CAR-T cell therapy [143]. Energetic efforts have been placed to improve CAR-T activity in solid tumors by building novel cellular constructs engineered to express immunostimulatory checkpoints including CD28 and OX-40 [144], specific tumor antigens [145][146][147] or effector cytokines such as IL-12, IL-18 [148]. These strategies have yielded promising efficacy in murine models engrafted with several tumors like melanoma, mesothelioma, neuroendocrine tumors as well as CRC [149].…”

Section: Future Prospects and Conclusionmentioning

confidence: 99%

Clinical Applications of Combined Immunotherapy Approaches in Gastrointestinal Cancer: A Case-Based Review

Eralp,

Ates

2023

Vaccines

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Malignant neoplasms arising from the gastrointestinal (GI) tract are among the most common types of cancer with high mortality rates. Despite advances in treatment in a small subgroup harboring targetable mutations, the outcome remains poor, accounting for one in three cancer-related deaths observed globally. As a promising therapeutic option in various tumor types, immunotherapy with immune checkpoint inhibitors has also been evaluated in GI cancer, albeit with limited efficacy except for a small subgroup expressing microsatellite instability. In the quest for more effective treatment options, energetic efforts have been placed to evaluate the role of several immunotherapy approaches comprising of cancer vaccines, adoptive cell therapies and immune checkpoint inhibitors. In this review, we report our experience with a personalized dendritic cell cancer vaccine and cytokine-induced killer cell therapy in three patients with GI cancers and summarize current clinical data on combined immunotherapy strategies.

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mRNAs encoding IL-12 and a decoy-resistant variant of IL-18 synergize to engineer T cells for efficacious intratumoral adoptive immunotherapy

Cited by 15 publications

References 90 publications

Tumor-associated CD8+T cell tolerance induced by erythroid progenitor cells

Tumor-associated CD8+T cell tolerance induced by erythroid progenitor cells

New insights into the stemness of adoptively transferred T cells by γc family cytokines

Clinical Applications of Combined Immunotherapy Approaches in Gastrointestinal Cancer: A Case-Based Review

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