Periodic Reporting for period 1 - ICD-Cancer (Immunogenic cell death (ICD) in the cancer-immune dialogue)
Okres sprawozdawczy: 2023-01-01 do 2025-06-30
The success of most if not all anticancer treatments depends on the (re)activation of immunosurveillance, as this has been documented for several therapeutic modalities, not only immunotherapy, but also chemotherapy, targeted therapy and radiotherapy. In response to antineoplastic drugs, malignant cells can undergo immunogenic cell death (ICD), thus exposing and releasing danger signals that act on pattern recognition receptors expressed by immune cells, in particular dendritic cells (DCs), to trigger the first steps of a therapeutically relevant anticancer immune response. Based on solid preliminary data and novel methodological approaches, we propose to obtain fundamental insights into the physicochemical properties and molecular mode of action of pharmacological ICD inducers (Task 1), to create chemical-genetic systems for “synthetic” ICD induction for the study of ICD effects on the immune system without perturbation by pleiotropic anticancer drugs (Task 2) and to identify new ICD-relevant immune checkpoints acting at the level of DCs (Task 3). We will use this knowledge to generate an integrated view of the cancer-immune dialogue ignited, on one side, by malignant cells succumbing to ICD and, on the other side, DCs perceiving ICD, hence developing optimal strategies for the stimulation of tumor immunosurveillance (Task 4). The concept of ICD has already been useful for patient-relevant biomarker discovery, drug development and trial design, strongly suggesting that a deeper exploration of this phenomenon will yield clinically relevant information.
The project advances exactly as planned with the following major achievements for each Task:
Task 1: We have identified several new drugs inducing immunogenic cell death (ICD):
The necrosis inducer necrocide 1 (Zhang et al. 2023 Cell Death Dis. PMID: 37015922)
The activator of adenosine 5'-monophosphate-activated protein kinase (AMPK) GSK621 (Mondesir et al. 2023 Blood Adv. PMID: 37903311)
The glutathione peroxidase 4 (GPX4) inducer N6F11 (Li et al. 2023. Sci Transl Med. PMID: 37910602)
The antidepressants sertraline and indraline (Alvarez-Valadez et al. 2024. Autophagy. PMID: 39663580)
Task 2: We advanced in the development of several artificial ("synthetic") systems related to ICD
We built an artificial ("synthetic") system to expose calreticulin on the surface of cancer cells in a biotin-inducible chemical genetic system.
We refined a phenotypic screening platform for the functional exploration of dendritic cells (DCs) using an artificial (or "synthetic") system of conditionally immortalized DC precursors
Task 3: Novel immune checkpoints in dendritic cells (DCs)
We identified TLR3 agonists such as TL-532 as activators of DC cell function (Le Naour et al. 2023 OncoImmunology, PMID: 37389102)
We pinpointed the hexokinase 2 inhibtor ikarugamycin as a DC activator (Zhang et al. 2023. J Immunother Cancer, PMID: 37419511)
We observed that the BCL2 inhibitor venetoclax blocks an immune checkpoint restricting antigen presentation by DCs (Zhao et al. 2023. Cancer Discov. PMID: 37623817)
Task 4:
We observed that astemizole acts as a histamine H1 receptor (H1R1) antagonist to activate T cells in a non-specific, DC-independent fashion (Zhang et al. 2023. J Immunother Cancer PMC10347457).
We found that high ACBP/DBI levels were predictive of future cancer development in still (apparently) health individuals and could demonstrate that ACBP/DBI neutralization with a monoclonal antibody improved the immune response against cancer cells in multiple mouse models of cancer (Montégut et al. 2024. Mol Cancer). Mechanistically, the immunostimulatory effects of anti-ACBP/DBI antibodies may be linked to their capacity to abolish the metabolic and immunosuppressive effects of glucocorticoids (Pan et al. 2024. Nat Metab. PMID: 39578649).
Task 1: We have identified several new drugs inducing immunogenic cell death (ICD):
The necrosis inducer necrocide 1 (Zhang et al. 2023 Cell Death Dis. PMID: 37015922)
The activator of adenosine 5'-monophosphate-activated protein kinase (AMPK) GSK621 (Mondesir et al. 2023 Blood Adv. PMID: 37903311)
The glutathione peroxidase 4 (GPX4) inducer N6F11 (Li et al. 2023. Sci Transl Med. PMID: 37910602)
The antidepressants sertraline and indraline (Alvarez-Valadez et al. 2024. Autophagy. PMID: 39663580)
Task 2: We advanced in the development of several artificial ("synthetic") systems related to ICD
We built an artificial ("synthetic") system to expose calreticulin on the surface of cancer cells in a biotin-inducible chemical genetic system.
We refined a phenotypic screening platform for the functional exploration of dendritic cells (DCs) using an artificial (or "synthetic") system of conditionally immortalized DC precursors
Task 3: Novel immune checkpoints in dendritic cells (DCs)
We identified TLR3 agonists such as TL-532 as activators of DC cell function (Le Naour et al. 2023 OncoImmunology, PMID: 37389102)
We pinpointed the hexokinase 2 inhibtor ikarugamycin as a DC activator (Zhang et al. 2023. J Immunother Cancer, PMID: 37419511)
We observed that the BCL2 inhibitor venetoclax blocks an immune checkpoint restricting antigen presentation by DCs (Zhao et al. 2023. Cancer Discov. PMID: 37623817)
Task 4:
We observed that astemizole acts as a histamine H1 receptor (H1R1) antagonist to activate T cells in a non-specific, DC-independent fashion (Zhang et al. 2023. J Immunother Cancer PMC10347457).
We found that high ACBP/DBI levels were predictive of future cancer development in still (apparently) health individuals and could demonstrate that ACBP/DBI neutralization with a monoclonal antibody improved the immune response against cancer cells in multiple mouse models of cancer (Montégut et al. 2024. Mol Cancer). Mechanistically, the immunostimulatory effects of anti-ACBP/DBI antibodies may be linked to their capacity to abolish the metabolic and immunosuppressive effects of glucocorticoids (Pan et al. 2024. Nat Metab. PMID: 39578649).
The finding that drugs such as ikarugamycin (Zhang et al. 2023. J Immunother Cancer. PMID: 37419511), and the BCL2 inhibitor venetoclax, see Zhao et al. 2023. Cancer Discovery. PMID: 37623817) can act on dendritic cells to stimulate immune responses against dying cancer cells appears unexpected and beyond state-of the art.
The finding that ACBP/DBI neutralization can improve cancer immunosurveillance (and increase immune responses against cancer cells that undergo immunogenic cell death) unravels the existence of a novel immune checkpoint (Montégut et al. 2024. Mol Cancer. PMID: 39242519). We apologize for this unexpected finding, yet want to insist that these results are embedded in a systematic characterization of the capacity of ACBP/DBI to favour the manifestation of age-related diseases and to subvert immunosuppression by glucocorticoids (Pan et al. 2024. Nat Metab. PMID: 39578649).
Similarly, the observation that immunogenic cell death is usually preceded by nucleolar condensation was based on AI-guided image analyses (Cerrato et al. 2024. Mol Cancer. PMID: 39702289).
The finding that ACBP/DBI neutralization can improve cancer immunosurveillance (and increase immune responses against cancer cells that undergo immunogenic cell death) unravels the existence of a novel immune checkpoint (Montégut et al. 2024. Mol Cancer. PMID: 39242519). We apologize for this unexpected finding, yet want to insist that these results are embedded in a systematic characterization of the capacity of ACBP/DBI to favour the manifestation of age-related diseases and to subvert immunosuppression by glucocorticoids (Pan et al. 2024. Nat Metab. PMID: 39578649).
Similarly, the observation that immunogenic cell death is usually preceded by nucleolar condensation was based on AI-guided image analyses (Cerrato et al. 2024. Mol Cancer. PMID: 39702289).