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Cytotoxic T cells are a vital component of the immune system. They have the remarkable ability to identify and target antigens on infected or abnormal cells. These antigens often originate from intracellular pathogens such as viruses or abnormal proteins cancer cells produce.
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Targeting Lysosomal Thiols for Immunogenic Cancer Cell Death.

Anton Arkhypov1, Insa Klemt1, Galyna Bila2,3

  • 1Friedrich-Alexander-University of Erlangen-Nürnberg (FAU), Department of Chemistry and Pharmacy, Organic Chemistry II, 91058, Erlangen, Germany.

Angewandte Chemie (International Ed. in English)
|November 4, 2024
PubMed
Summary
This summary is machine-generated.

A novel therapeutic agent, reversible thiol binder 11, targets cancer cell lysosomes, inducing cell death and potent anti-tumor immunity. This approach shows significant efficacy in preclinical models, offering a promising new avenue for cancer therapy.

Keywords:
CancerElectrophilic DrugImmunogenic Cell DeathIntracellular ThiolLysosome

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Area of Science:

  • Oncology
  • Immunology
  • Cell Biology

Background:

  • Lysosomes (LYs) exhibit altered number and stability in cancer cells, presenting a therapeutic target.
  • Current therapies lack approved drugs that specifically target lysosomes for cancer treatment.

Purpose of the Study:

  • To investigate a novel therapeutic strategy using a reversible thiol binder (compound 11) to target cancer cell lysosomes.
  • To evaluate the efficacy and immune response induced by compound 11 in a preclinical cancer model.

Main Methods:

  • Treatment of cancer cells with compound 11 to induce lysosomal thiol alkylation.
  • Assessment of lysosomal reactive oxygen species (ROS) levels, lysosomal stability, and cancer cell death.
  • Evaluation of therapeutic effects in the murine sarcoma Nemeth-Kellner (NK)/Ly-RB model.
  • Analysis of humoral immune response and neutrophil activity in cured mice.

Main Results:

  • Compound 11 treatment increased lysosomal ROS, leading to destabilization, disruption, and immunogenic cancer cell death.
  • In the NK/Ly-RB model, compound 11 extended median survival from 21 to 85 days and cured 40% of mice.
  • Cured mice developed antibodies against tumor cells and exhibited 100% survival upon re-challenge, indicating acquired immunity.
  • Neutrophils in cured mice demonstrated anti-tumor activity via neutrophil extracellular traps (NETs).

Conclusions:

  • Compound 11 demonstrates direct anti-tumor effects by inducing lysosomal damage and immunogenic cell death.
  • The therapy primes both humoral and neutrophil-mediated immune responses against cancer cells.
  • This lysosome-targeting approach represents a promising strategy for cancer-specific therapy.