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Published on: June 14, 2024
Balancing between antitumor efficacy and autoimmune pathology in T-cell-mediated targeting of carcinoembryonic
Rinke Bos1, Suzanne van Duikeren, Hans Morreau
1Department of Immunohematology and Blood Transfusion, Tumor Immunology Group, Leiden University Medical Center, Leiden, the Netherlands.
Abstract:
Carcinoembryonic antigen (CEA) is intensively studied as a potential target for immunotherapy of colorectal cancers. Although overexpressed by tumors, CEA is also expressed in normal tissues, raising questions about the feasibility and safety of CEA-targeted immunotherapy. We investigated these issues in transgenic mice in which the expression of human CEA in normal tissues closely resembles that in man. Our data show that the T-cell response against CEA in these mice is blunted by both thymic and peripheral tolerance. Consequently, effective tumor targeting is only achieved by adoptive transfer of T cells from nontolerant donors in combination with interventions that eliminate peripheral immune regulatory mechanisms. However, such treatments can result in severe intestinal autoimmune pathology associated with weight loss and mortality. Interestingly, preconditioning of recipient mice by depletion of T-regulatory cells results in immune-mediated tumor control in the absence of toxicity. In this setting, CEA-specific T-cell responses are lower than those induced by toxic regimens and accompanied by additional T-cell responses against non-self antigen. These findings illustrate the importance of testing adoptive immunotherapies targeting self antigens such as CEA in preclinical in vivo models and show that the choice of immune intervention regimen critically determines the balance between therapeutic efficacy and toxicity.
Insights
Targeting carcinoembryonic antigen (CEA) for colorectal cancer immunotherapy is challenging due to self-tolerance. Depleting regulatory T-cells in mice offers a promising strategy for effective tumor control without toxicity.
Area of Science:
- Immunology
- Oncology
- Transgenic animal models
Background:
- Carcinoembryonic antigen (CEA) is a tumor-associated antigen investigated for colorectal cancer immunotherapy.
- CEA expression in normal tissues raises concerns regarding the safety and feasibility of CEA-targeted therapies due to potential autoimmunity.
Purpose of the Study:
- To investigate the challenges and potential solutions for CEA-targeted immunotherapy in colorectal cancer.
- To evaluate the safety and efficacy of different immune intervention strategies in preclinical models.
Main Methods:
- Utilized transgenic mice with human CEA expression in normal tissues mirroring human expression patterns.
- Assessed T-cell responses against CEA under conditions of thymic and peripheral tolerance.
- Investigated adoptive T-cell transfer combined with immune regulatory mechanism elimination and T-regulatory cell depletion.
Main Results:
- T-cell responses against CEA were suppressed by thymic and peripheral tolerance in transgenic mice.
- Adoptive T-cell transfer with elimination of peripheral immune regulation led to tumor targeting but caused severe autoimmune pathology.
- Preconditioning with T-regulatory cell depletion resulted in effective tumor control without toxicity, with lower CEA-specific T-cell responses.
Conclusions:
- Preclinical models are crucial for evaluating adoptive immunotherapies targeting self-antigens like CEA.
- The choice of immune intervention regimen critically influences the balance between therapeutic efficacy and toxicity in CEA-targeted immunotherapy.
- T-regulatory cell depletion presents a potentially safe and effective strategy for CEA-targeted cancer immunotherapy.
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