Combined PD-L1 and TIM3 blockade improves expansion of fit human CD8+ antigen-specific T cells for adoptive immunotherapy

Lak, Shirin; Janelle, Valérie; Djedid, Anissa; Boudreau, Ginette; Brasey, Ann; Lisi, Véronique; Smaani, Ali; Carli, Cédric; Busque, Lambert; Lavallée, Vincent-Philippe; Delisle, Jean-Sébastien

doi:10.1016/j.omtm.2022.09.016

Cited by 6 publications

(3 citation statements)

References 48 publications

(61 reference statements)

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“…However, consistent with the results in Figure 1C, the combined LL-37 treatments produced a significant enhancement in the proportions of CD8 + T cells in the DC-stimulated lymphocytes (Figure 2C,D). NK cells and T cells are often associated with the increased expression of inhibitory molecules PD-1 and TIM-3, whose blockade with anti-PD-1 and/or anti-TIM-3 blocking antibodies improves the functionality of these cells [23][24][25]. Our analyses revealed that LL-37 significantly decreased the frequency of PD-1-expressing CD8 + T cells in the DC-stimulated lymphocytes.…”

Section: Ll-37 Was Important For Both DC Differentiation and Pulsatio...mentioning

confidence: 60%

LL-37 as a Powerful Molecular Tool for Boosting the Performance of Ex Vivo-Produced Human Dendritic Cells for Cancer Immunotherapy

et al. 2022

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Ex vivo-produced dendritic cells (DCs) constitute the core of active cellular immunotherapy (ACI) for cancer treatment. After many disappointments in clinical trials, the current protocols for their preparation are attempting to boost their therapeutic efficacy by enhancing their functionality towards Th1 response and capability to induce the expansion of cytotoxic tumor-specific CD8+ T cells. LL-37 is an antimicrobial peptide with strong immunomodulatory potential. This potential was previously found to either enhance or suppress the desired anti-tumor DC functionality when used at different phases of their ex vivo production. In this work, we show that LL-37 can be implemented during the whole process of DC production in a way that allows LL-37 to enhance the anti-tumor functionality of produced DCs. We found that the supplementation of LL-37 during the differentiation of monocyte-derived DCs showed only a tendency to enhance their in vitro-induced lymphocyte enrichment with CD8+ T cells. The supplementation of LL-37 also during the process of DC antigen loading (pulsation) and maturation significantly enhanced the cell culture enrichment with CD8+ T cells. Moreover, this enrichment was also associated with the downregulated expression of PD-1 in CD8+ T cells, significantly higher frequency of tumor cell-reactive CD8+ T cells, and superior in vitro cytotoxicity against tumor cells. These data showed that LL-37 implementation into the whole process of the ex vivo production of DCs could significantly boost their anti-tumor performance in ACI.

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Section: Ll-37 Was Important For Both DC Differentiation and Pulsatio...mentioning

confidence: 60%

LL-37 as a Powerful Molecular Tool for Boosting the Performance of Ex Vivo-Produced Human Dendritic Cells for Cancer Immunotherapy

et al. 2022

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“…In this context, the in vitro study of combined PD-L1 and TIM-3 blockade indicates enhanced expansion of fit human CD8 + antigen-specific T cells for adoptive immunotherapy. 43 Recently, various clinical trials include TIM-3 as a novel target in cancer immunotherapy. Ongoing clinical trials with Tim-3-specific monoclonal antibodies or antagonist agents are presented in Table 1 .…”

Section: T-cell Immunoglobulin and Mucin Domainmentioning

confidence: 99%

Immune checkpoints and cancer immunotherapies: insights into newly potential receptors and ligands

Kamali,

Bautista,

Eisenhut

et al. 2023

Therapeutic Advances in Vaccines and Immunotherapy

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Checkpoint markers and immune checkpoint inhibitors have been increasingly identified and developed as potential immunotherapeutic targets in various human cancers. Despite valuable efforts to discover novel immune checkpoints and their ligands, the precise roles of their therapeutic functions, as well as the broad identification of their counterpart receptors, remain to be addressed. In this context, it has been suggested that various putative checkpoint receptors can be induced upon activation. In the tumor microenvironment, T cells, as crucial immune response against malignant diseases as well as other immune central effector cells, such as natural killer cells, are regulated via co-stimulatory or co-inhibitory signals from immune or tumor cells. Studies have shown that exposure of T cells to tumor antigens upregulates the expression of inhibitory checkpoint receptors, leading to T-cell dysfunction or exhaustion. Although targeting immune checkpoint regulators has shown relative clinical efficacy in some tumor types, most trials in the field of cancer immunotherapies have revealed unsatisfactory results due to de novo or adaptive resistance in cancer patients. To overcome these obstacles, combinational therapies with newly discovered inhibitory molecules or combined blockage of several checkpoints provide a rationale for further research. Moreover, precise identification of their receptors counterparts at crucial checkpoints is likely to promise effective therapies. In this review, we examine the prospects for the application of newly emerging checkpoints, such as T-cell immunoglobulin and mucin domain 3, lymphocyte activation gene-3, T-cell immunoreceptor with Ig and ITIM domains (TIGIT), V-domain Ig suppressor of T-cell activation (VISTA), new B7 family proteins, and B- and T-cell lymphocyte attenuator, in association with immunotherapy of malignancies. In addition, their clinical and biological significance is discussed, including their expression in various human cancers, along with their roles in T-cell-mediated immune responses.

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“…demonstrate that blocking both programmed death-ligand 1 (PD-L1) and T cell immunoglobulin and mucin-containing protein 3 (TIM-3) during the generation of antigen-specific CD8 + T cells led to improved T cell expansion without inducing T cell dysfunction, but only when blockade was induced with specific timing. 4 This “delayed double blockade,” or DDB, did not seem to induce changes in gene expression or T cell receptor (TCR) repertoire in expanded T cells. These findings suggest a translatable strategy for improving the manufacturing of adoptively transferred antigen-specific T cells.…”

mentioning

confidence: 98%

Spacing out dual checkpoint inhibition improves antigen-specific T cell manufacture

Wang¹,

Wang²

2023

Molecular Therapy - Methods & Clinical Development

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Combined PD-L1 and TIM3 blockade improves expansion of fit human CD8+ antigen-specific T cells for adoptive immunotherapy

Cited by 6 publications

References 48 publications

LL-37 as a Powerful Molecular Tool for Boosting the Performance of Ex Vivo-Produced Human Dendritic Cells for Cancer Immunotherapy

LL-37 as a Powerful Molecular Tool for Boosting the Performance of Ex Vivo-Produced Human Dendritic Cells for Cancer Immunotherapy

Immune checkpoints and cancer immunotherapies: insights into newly potential receptors and ligands

Spacing out dual checkpoint inhibition improves antigen-specific T cell manufacture

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