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Multi-omic profiling reveals the endogenous and neoplastic responses to immunotherapies in cutaneous T cell lymphoma
David R Glass1, Koshlan Mayer-Blackwell1, Nirasha Ramchurren2
1Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Abstract:
Cutaneous T cell lymphomas (CTCLs) are skin cancers with poor survival rates and limited treatments. While immunotherapies have shown some efficacy, the immunological consequences of administering immune-activating agents to CTCL patients have not been systematically characterized. We apply a suite of high-dimensional technologies to investigate the local, cellular, and systemic responses in CTCL patients receiving either mono- or combination anti-PD-1 plus interferon-gamma (IFN-γ) therapy. Neoplastic T cells display no evidence of activation after immunotherapy. IFN-γ induces muted endogenous immunological responses, while anti-PD-1 elicits broader changes, including increased abundance of CLA+CD39+ T cells. We develop an unbiased multi-omic profiling approach enabling discovery of immune modules stratifying patients. We identify an enrichment of activated regulatory CLA+CD39+ T cells in non-responders and activated cytotoxic CLA+CD39+ T cells in leukemic patients. Our results provide insights into the effects of immunotherapy in CTCL patients and a generalizable framework for multi-omic analysis of clinical trials.
Insights
Immunotherapy for cutaneous T-cell lymphoma (CTCL) shows limited T-cell activation. Anti-PD-1 therapy increases specific T-cell types, offering insights into treatment responses in these skin cancers.
Area of Science:
- Oncology
- Immunology
- Dermatology
Background:
- Cutaneous T-cell lymphomas (CTCL) are aggressive skin cancers with poor prognoses.
- Current immunotherapies offer limited efficacy, and their immunological effects in CTCL patients remain poorly understood.
Purpose of the Study:
- To systematically characterize the local, cellular, and systemic immunological responses in CTCL patients undergoing anti-PD-1 and/or interferon-gamma (IFN-γ) therapy.
- To identify immune signatures associated with treatment response or non-response.
Main Methods:
- Utilized high-dimensional technologies for multi-omic profiling of CTCL patient samples.
- Applied an unbiased approach to analyze immune cell populations and molecular changes post-immunotherapy.
Main Results:
- Neoplastic T-cells showed no significant activation post-immunotherapy.
- IFN-γ induced minimal endogenous immune responses, while anti-PD-1 therapy increased CLA+CD39+ T-cells.
- Distinct immune modules were identified, with activated regulatory CLA+CD39+ T-cells enriched in non-responders and activated cytotoxic CLA+CD39+ T-cells in leukemic CTCL patients.
Conclusions:
- The study provides crucial insights into the immunological impact of immunotherapy in CTCL.
- Developed a generalizable multi-omic framework for analyzing clinical trial data in cancer immunotherapy.
- Identified specific T-cell subsets that may serve as biomarkers for predicting treatment outcomes in CTCL.
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