Targeting PI3K-gamma in myeloid driven tumour immune suppression: a systematic review and meta-analysis of the preclinical literature DOI Creative Commons
Haonan Xu,

Shannon Nicole Russell,

Katherine Steiner

et al.

Cancer Immunology Immunotherapy, Journal Year: 2024, Volume and Issue: 73(10)

Published: Aug. 6, 2024

Abstract The intricate interplay between immune and stromal cells within the tumour microenvironment (TME) significantly influences progression. Myeloid cells, including tumour-associated macrophages (TAMs), neutrophils (TANs), myeloid-derived suppressor (MDSCs), contribute to suppression in TME (Nakamura Smyth Cell Mol Immunol 17(1):1–12 (2020). https://doi.org/10.1038/s41423-019-0306-1 ; DeNardo Ruffell Nat Rev 19(6):369–382 (2019). https://doi.org/10.1038/s41577-019-0127-6 ). This poses a significant challenge for novel immunotherapeutics that rely on host immunity exert their effect. systematic review explores preclinical evidence surrounding inhibition of phosphoinositide 3-kinase gamma (PI3Kγ) as strategy reverse myeloid-driven solid tumours. EMBASE, MEDLINE, PubMed databases were searched 6 October 2022 using keyword subject heading terms capture relevant studies. studies, focusing PI3Kγ animal models, subjected predefined inclusion exclusion criteria. Extracted data included growth kinetics, survival endpoints, immunological responses which meta-analysed. PRISMA MOOSE guidelines followed. A total 36 studies covering 73 models meta-analysis. Tumour covered breast, colorectal, lung, skin, pancreas, brain, liver, prostate, head neck, soft tissue, gastric, oral cancer. predominant inhibitors IPI-549 TG100-115, demonstrating favourable specificity isoform. Combination therapies, often involving chemotherapy, radiotherapy, checkpoint inhibitors, biological agents, or vaccines, explored 81% Analysis kinetics revealed statistically though heterogeneous response monotherapy, whereas combination treated groups more consistently reduced. Survival analysis showed pronounced increase median overall with therapy. provides comprehensive investigating suppression. identified underscore potential reshaping by modulating myeloid cell functions. other therapeutic modalities demonstrated enhanced antitumour effects, suggesting synergistic approach overcome These findings support PI3Kγ-targeted particularly regimens, promising avenue future clinical exploration diverse types. Graphical abstract

Language: Английский

Bone marrow breakout lesions act as key sites for tumor-immune cell diversification in multiple myeloma DOI Open Access

Raphael Lutz,

Alexandra M. Poos,

Llorenç Solé‐Boldo

et al.

Science Immunology, Journal Year: 2025, Volume and Issue: 10(104)

Published: Feb. 7, 2025

The bone marrow microenvironment plays a crucial role in the development of multiple myeloma. As disease progresses, malignant myeloma cells can evolve to survive outside marrow. However, processes underlying independence and their consequences for immune control remain poorly understood. Here, we conducted single-cell spatial multiomics analyses marrow-confined intramedullary paired breakout lesions that disrupt cortical bone. These revealed distinct cellular architectural features lesions, characterized by extensive areas plasma interspersed with lesion-specific solitary natural killer macrophage populations, as well focal accumulations cell agglomerates. Within these agglomerates, spatially confined T clones expanded alongside various cells, coinciding local genomic evolution tumor cells. identify hotspot tumor-immune interactions diversification, representing key event pathogenesis.

Language: Английский

Citations

1
Tri-specific tribodies targeting 5T4, CD3, and immune checkpoint drive stronger functional T-cell responses than combinations of antibody therapeutics DOI Creative Commons
Margherita Passariello,

Lorenzo Manna,

Rosa Rapuano Lembo

et al.

Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: Feb. 10, 2025

Abstract One of the most promising cancer immunotherapies is based on bi-specific T-cell engagers (BiTEs) that simultaneously bind with one arm to a tumor-associated antigen tumor cells and other CD3 complex T form TCR-MHC independent immune synapse. We previously generated four novel tri-specific tribodies made up Fab targeting 5T4, an oncofetal expressed several types tumors, scFv cells, additional specific for checkpoint (IC), such as PD-1, PD-L1 or LAG-3. To verify their advantages over combinations BiTEs (CD3/TAA) IC inhibitors, recently used overcome immunosuppressive environment, here we tested functional properties in comparison clinically validated mAbs same ICs, alone combination control devoid immunomodulatory scFvs, called 53 P. found activated human peripheral blood mononuclear more efficiently than (atezolizumab, pembrolizumab, relatlimab) either P, leading stronger cytotoxicity cytokines release. In particular, 53L10 tribody displayed much potent effects P all led complete regression vivo, showing higher efficacy atezolizumab. shed light molecular basis this potentiated anti-tumor activity by evidencing insertion anti-PD-L1 moiety not only binding but also blocked increased induced IFNγ secretion due activation. These results are important design antigens.

Language: Английский

Citations

1
Microenvironment-based immunotherapy in oral cancer: a comprehensive review DOI

Hassan Mivehchi,

Aisan Eskandari-Yaghbastlo,

Masumeh Ghazanfarpour

et al.

Medical Oncology, Journal Year: 2025, Volume and Issue: 42(5)

Published: March 28, 2025

Language: Английский

Citations

1
Anti-PD-L1-Based Bispecific Antibodies Targeting Co-Inhibitory and Co-Stimulatory Molecules for Cancer Immunotherapy DOI Creative Commons

Qiaohong Geng,

Peifu Jiao

Molecules, Journal Year: 2024, Volume and Issue: 29(2), P. 454 - 454

Published: Jan. 17, 2024

Targeting PD-L1 via monospecific antibodies has shown durable clinical benefits and long-term remissions where patients exhibit no cancer signs for many years after treatment. However, the by anti-PD-L1 monotherapy have been limited to a small fraction of with certain types. bispecific (referred as anti-PD-L1-based bsAbs) which can simultaneously bind both co-inhibitory co-stimulatory molecules may increase antitumor responses in who would not benefit from monotherapy. A growing number bsAbs developed fight against this deadly disease. This review summarizes recent advances immunotherapy patents literatures, discusses their anti-tumor efficacies vitro vivo. Over 50 targeting investigated biological testing or trials since 2017. At least eleven proteins, such CTLA-4, LAG-3, PD-1, PD-L2, TIM-3, TIGIT, CD28, CD27, OX40, CD137, ICOS, are involved these investigations. Twenty-two being evaluated treat various advanced cancers trials, wherein indications include NSCLC, SNSCLC, SCLC, PDA, MBNHL, SCCHN, UC, EC, TNBC, CC, some other malignancies. The released data indicated that most were well-tolerated showed promising efficacy solid tumors. approved investigational much more significant adverse reactions compared antibodies, be further optimized molecular structure modification avoid reduce reactions.

Language: Английский

Citations

8
Targeting PI3K-gamma in myeloid driven tumour immune suppression: a systematic review and meta-analysis of the preclinical literature DOI Creative Commons
Haonan Xu,

Shannon Nicole Russell,

Katherine Steiner

et al.

Cancer Immunology Immunotherapy, Journal Year: 2024, Volume and Issue: 73(10)

Published: Aug. 6, 2024

Abstract The intricate interplay between immune and stromal cells within the tumour microenvironment (TME) significantly influences progression. Myeloid cells, including tumour-associated macrophages (TAMs), neutrophils (TANs), myeloid-derived suppressor (MDSCs), contribute to suppression in TME (Nakamura Smyth Cell Mol Immunol 17(1):1–12 (2020). https://doi.org/10.1038/s41423-019-0306-1 ; DeNardo Ruffell Nat Rev 19(6):369–382 (2019). https://doi.org/10.1038/s41577-019-0127-6 ). This poses a significant challenge for novel immunotherapeutics that rely on host immunity exert their effect. systematic review explores preclinical evidence surrounding inhibition of phosphoinositide 3-kinase gamma (PI3Kγ) as strategy reverse myeloid-driven solid tumours. EMBASE, MEDLINE, PubMed databases were searched 6 October 2022 using keyword subject heading terms capture relevant studies. studies, focusing PI3Kγ animal models, subjected predefined inclusion exclusion criteria. Extracted data included growth kinetics, survival endpoints, immunological responses which meta-analysed. PRISMA MOOSE guidelines followed. A total 36 studies covering 73 models meta-analysis. Tumour covered breast, colorectal, lung, skin, pancreas, brain, liver, prostate, head neck, soft tissue, gastric, oral cancer. predominant inhibitors IPI-549 TG100-115, demonstrating favourable specificity isoform. Combination therapies, often involving chemotherapy, radiotherapy, checkpoint inhibitors, biological agents, or vaccines, explored 81% Analysis kinetics revealed statistically though heterogeneous response monotherapy, whereas combination treated groups more consistently reduced. Survival analysis showed pronounced increase median overall with therapy. provides comprehensive investigating suppression. identified underscore potential reshaping by modulating myeloid cell functions. other therapeutic modalities demonstrated enhanced antitumour effects, suggesting synergistic approach overcome These findings support PI3Kγ-targeted particularly regimens, promising avenue future clinical exploration diverse types. Graphical abstract

Language: Английский

Citations

8