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Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
Targeting tumor-resident mast cells for effective anti-melanoma immune responses
Susanne Kaesler1,2, Florian Wölbing1,2, Wolfgang Eberhard Kempf1
1Department of Dermatology and Allergy, School of Medicine, Technical University of Munich, Munich, Germany.
Abstract:
Immune checkpoint blockade has revolutionized cancer treatment. Patients developing immune mediated adverse events, such as colitis, appear to particularly benefit from immune checkpoint inhibition. Yet, the contributing mechanisms are largely unknown. We identified a systemic LPS signature in melanoma patients with colitis following anti-cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4) checkpoint inhibitor treatment and hypothesized that intestinal microbiota-derived LPS contributes to therapeutic efficacy. Because activation of immune cells within the tumor microenvironment is considered most promising to effectively control cancer, we analyzed human and murine melanoma for known sentinels of LPS. We identified mast cells (MCs) accumulating in and around melanomas and showed that effective melanoma immune control was dependent on LPS-activated MCs recruiting tumor-infiltrating effector T cells by secretion of CXCL10. Importantly, CXCL10 was also upregulated in human melanomas with immune regression and in patients with colitis induced by anti-CTLA-4 antibody. Furthermore, we demonstrate that CXCL10 upregulation and an MC signature at the site of melanomas are biomarkers for better patient survival. These findings provide conclusive evidence for a "Trojan horse treatment strategy" in which the plasticity of cancer-resident immune cells, such as MCs, is used as a target to boost tumor immune defense.
Insights
Immune checkpoint inhibitors like anti-CTLA-4 may improve cancer treatment by activating mast cells (MCs) with lipopolysaccharide (LPS). This LPS-activated MCs recruit T cells, boosting anti-tumor immunity and improving patient survival.
Area of Science:
- Immunology
- Oncology
- Microbiome Research
Background:
- Immune checkpoint blockade, particularly anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) therapy, has transformed cancer treatment.
- Immune-mediated adverse events, such as colitis, are associated with improved responses to immune checkpoint inhibition, but the underlying mechanisms remain unclear.
- A systemic lipopolysaccharide (LPS) signature was observed in melanoma patients experiencing colitis after anti-CTLA-4 treatment, suggesting a role for microbiota-derived LPS.
Purpose of the Study:
- To investigate the role of intestinal microbiota-derived LPS in the therapeutic efficacy of anti-CTLA-4 therapy.
- To identify immune cells and mechanisms within the tumor microenvironment that contribute to anti-CTLA-4 therapy's effectiveness.
- To explore potential biomarkers for predicting patient survival and treatment response.
Main Methods:
- Analysis of human and murine melanoma for LPS sentinels.
- Identification and characterization of mast cells (MCs) in melanoma tumors.
- Assessment of T-cell infiltration and cytokine secretion (CXCL10) in response to LPS-activated MCs.
- Correlation of CXCL10 and MC signatures with clinical outcomes in melanoma patients.
Main Results:
- Mast cells (MCs) were found to accumulate in and around melanomas.
- Effective melanoma immune control was dependent on LPS-activated MCs recruiting tumor-infiltrating effector T cells via CXCL10 secretion.
- CXCL10 was upregulated in human melanomas exhibiting immune regression and in patients with anti-CTLA-4-induced colitis.
- Upregulation of CXCL10 and an MC signature in melanomas served as biomarkers for improved patient survival.
Conclusions:
- LPS-activated mast cells (MCs) play a crucial role in mediating the anti-tumor immune response by recruiting effector T cells through CXCL10 secretion.
- The findings support a "Trojan horse treatment strategy" that leverages the plasticity of cancer-resident immune cells like MCs to enhance anti-tumor immunity.
- CXCL10 and MC signatures are promising biomarkers for predicting patient survival and response to immune checkpoint inhibition in melanoma.
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