Gene-based delivery of immune-activating cytokines for cancer treatment

Rossari, Federico; Birocchi, Filippo; Naldini, Luigi; Coltella, Nadia

doi:10.1016/j.molmed.2023.01.006

Cited by 10 publications

(4 citation statements)

References 107 publications

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“…The immunologic TME plays a vital role in the development of CRC, where resident cells communicate with neighboring cells through soluble factors, such as cytokines or chemokines, to produce a pro-tumor or anti-tumor immune response ( 39 ). Our results are consistent with those of previous studies that reported elevated levels of several circulating cytokines in cancer patients, namely increased concentrations of cytokines MIF, TNF-α, IL-6, IL-8, IL-17, IL-23, IL-10, and TGF-β in the peripheral blood of cancer patients, leading to simultaneous immune activation and immunosuppression in cancer patients ( 40 , 41 ).…”

Section: Discussionmentioning

confidence: 99%

Cytokine concentration in peripheral blood of patients with colorectal cancer

Chen

Gao

et al. 2023

Front. Immunol.

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IntroductionThe role of tumour secretory cytokines and peripheral circulatory cytokines in tumour progression has received increasing attention; however, the role of tumour-related inflammatory cytokines in colorectal cancer (CRC) remains unclear. In this study, the concentrations of various cytokines in the peripheral blood of healthy controls and patients with CRC at different stages were compared.MethodsPeripheral blood samples from 4 healthy participants and 22 colorectal cancer patients were examined. Luminex beads were used to evaluate concentration levels of 40 inflammatory cytokines in peripheral blood samples.ResultsIn peripheral blood, compared with healthy controls and early stage (I + II) CRC patients, advanced CRC (III + IV) patients had increased concentrations of mononuclear/macrophage chemotactic-related proteins (CCL7, CCL8, CCL15, CCL2, and MIF), M2 polarization-related factors (IL-1β, IL-4), neutrophil chemotactic and N2 polarization-related cytokines (CXCL2, CXCL5, CXCL6, IL-8), dendritic cells (DCs) chemotactic-related proteins (CCL19, CCL20, and CCL21), Natural killer (NK) cell related cytokines (CXCL9, CXCL10), Th2 cell-related cytokines (CCL1, CCL11, CCL26), CXCL12, IL-2, CCL25, and CCL27, and decreased IFN-γ and CX3CL1 concentrations. The differential upregulation of cytokines in peripheral blood was mainly concentrated in CRC patients with distant metastasis and was related to the size of the primary tumour; however, there was no significant correlation between cytokine levels in peripheral blood and the propensity and mechanism of lymph node metastasis.DiscussionDifferent types of immune cells may share the same chemokine receptors and can co-localise in response to the same chemokines and exert synergistic pro-tumour or anti-tumour functions in the tumour microenvironment. Chemokines and cytokines affect tumour metastasis and prognosis and may be potential targets for treatment.

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Section: Discussionmentioning

confidence: 99%

Cytokine concentration in peripheral blood of patients with colorectal cancer

Chen

Gao

et al. 2023

Front. Immunol.

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“…We and others have previously illustrated the therapeutic potential of myeloid cells engineered to express immune-activating cytokines, such as IFNα and IL-12, in mouse cancer models 65 – 69 . Earlier approaches differ from our strategy in several ways, such as the use of hematopoietic progenitors with broad myeloid-cell differentiation or the need for host conditioning to enable sustained cytokine delivery by transduced cells.…”

Section: Discussionmentioning

confidence: 99%

Cytokine-armed dendritic cell progenitors for antigen-agnostic cancer immunotherapy

Ghasemi,

Martinez-Usatorre,

et al. 2023

Nat Cancer

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Dendritic cells (DCs) are antigen-presenting myeloid cells that regulate T cell activation, trafficking and function. Monocyte-derived DCs pulsed with tumor antigens have been tested extensively for therapeutic vaccination in cancer, with mixed clinical results. Here, we present a cell-therapy platform based on mouse or human DC progenitors (DCPs) engineered to produce two immunostimulatory cytokines, IL-12 and FLT3L. Cytokine-armed DCPs differentiated into conventional type-I DCs (cDC1) and suppressed tumor growth, including melanoma and autochthonous liver models, without the need for antigen loading or myeloablative host conditioning. Tumor response involved synergy between IL-12 and FLT3L and was associated with natural killer and T cell infiltration and activation, M1-like macrophage programming and ischemic tumor necrosis. Antitumor immunity was dependent on endogenous cDC1 expansion and interferon-γ signaling but did not require CD8+ T cell cytotoxicity. Cytokine-armed DCPs synergized effectively with anti-GD2 chimeric-antigen receptor (CAR) T cells in eradicating intracranial gliomas in mice, illustrating their potential in combination therapies.

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“…Viral vector-mediated delivery or adoptive transfer of genetically modified cells has been shown to enhance the expression of molecules at the anatomical target site. Many studies employ viral vectors carrying cytokines and gene-modified immune cells to induce TLS in preclinical and early-stage clinical studies ( 52 ). Critical considerations of a viral vector-based strategy include the selection of the optimal cell in the TME that can be targeted to generate stable and functional TLS at the tumor site.…”

Section: Induction Of Tls: Current and Potential Strategiesmentioning

confidence: 99%

“…In addition, LVs are efficient vehicles for introducing and stably expressing effector molecules in healthy human cells, tumor cells, and immune and non-immune cells ( 57 , 64 – 66 ). Moreover, LVs have extensive plasticity to accommodate several genes and regulatory sequences ( 52 ). For example, LVs have been used to deliver engineered CAR-T cells expressing CCL19 and IL-7 to promote TME infiltration and enhance antitumor response ( 67 – 69 ).…”

Section: Induction Of Tls: Current and Potential Strategiesmentioning

confidence: 99%

Epigenetic targets to enhance antitumor immune response through the induction of tertiary lymphoid structures

Omotesho,

Escamilla,

Pérez-Ruiz

et al. 2024

Front. Immunol.

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Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates found in sites of chronic inflammation such as tumors and autoimmune diseases. The discovery that TLS formation at tumor sites correlated with good patient prognosis has triggered extensive research into various techniques to induce their formation at the tumor microenvironment (TME). One strategy is the exogenous induction of specific cytokines and chemokine expression in murine models. However, applying such systemic chemokine expression can result in significant toxicity and damage to healthy tissues. Also, the TLS formed from exogenous chemokine induction is heterogeneous and different from the ones associated with favorable prognosis. Therefore, there is a need to optimize additional approaches like immune cell engineering with lentiviral transduction to improve the TLS formation in vivo. Similarly, the genetic and epigenetic regulation of the different phases of TLS neogenesis are still unknown. Understanding these molecular regulations could help identify novel targets to induce tissue-specific TLS in the TME. This review offers a unique insight into the molecular checkpoints of the different stages and mechanisms involved in TLS formation. This review also highlights potential epigenetic targets to induce TLS neogenesis. The review further explores epigenetic therapies (epi-therapy) and ongoing clinical trials using epi-therapy in cancers. In addition, it builds upon the current knowledge of tools to generate TLS and TLS phenotyping biomarkers with predictive and prognostic clinical potential.

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Gene-based delivery of immune-activating cytokines for cancer treatment

Cited by 10 publications

References 107 publications

Cytokine concentration in peripheral blood of patients with colorectal cancer

Cytokine concentration in peripheral blood of patients with colorectal cancer

Cytokine-armed dendritic cell progenitors for antigen-agnostic cancer immunotherapy

Epigenetic targets to enhance antitumor immune response through the induction of tertiary lymphoid structures

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