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Evaluation of Tumor-infiltrating Leukocyte Subsets in a Subcutaneous Tumor Model
Published on: April 13, 2015
Skin Infiltrate Composition as a Telling Measure of Responses to Checkpoint Inhibitors
Cory Kosche1, Dinesh Jaishankar1,2, Cormac Cosgrove1,2
1Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Abstract:
Checkpoint inhibitors treat a variety of tumor types with significant benefits. Unfortunately, these therapies come with diverse adverse events. Skin rash is observed early into treatment and might serve as an indicator of downstream responses to therapy. We studied the cellular composition of cutaneous eruptions and whether their contribution varies with the treatment applied. Skin samples from 18 patients with cancer and 11 controls were evaluated by mono- and multiplex imaging, quantification, and statistical analysis. T cells were the prime contributors to skin rash, with T cells and macrophages interacting and proliferating on site. Among T cell subsets examined, type 1 and 17 T cells were relatively increased among inflammatory skin infiltrates. A combination of increased cytotoxic T cell content and decreased macrophage abundance was associated with dual checkpoint inhibition over PD1 inhibition alone. Importantly, responders significantly separated from nonresponders by greater CD68+ macrophage and either CD11c+ antigen-presenting cell or CD4+ T cell abundance in skin rash. The microenvironment promoted epidermal proliferation and thickening as well. The combination of checkpoint inhibitors used affects the development and composition of skin infiltrates, whereas the combined abundance of two cell types in cutaneous eruptions aligns with responses to checkpoint inhibitor therapy.
Insights
Checkpoint inhibitors can cause skin rash, an early indicator of treatment response. This study found T cells and macrophages drive rash, with specific cell types correlating to treatment effectiveness in cancer patients.
Area of Science:
- Immunology
- Dermatology
- Oncology
Background:
- Checkpoint inhibitors offer significant benefits for various cancers.
- Adverse events, including skin rash, are common with these therapies.
- Skin rash may predict treatment response.
Purpose of the Study:
- To investigate the cellular composition of checkpoint inhibitor-induced skin rash.
- To determine if cellular composition varies with different checkpoint inhibitor treatments.
- To correlate rash cellularity with patient response to therapy.
Main Methods:
- Analysis of skin biopsy samples from cancer patients and controls.
- Utilized mono- and multiplex imaging for cellular quantification.
- Employed statistical analysis to compare patient groups and treatment types.
Main Results:
- T cells were the primary cellular component of skin rash, interacting with macrophages.
- Increased type 1 and 17 T cells were observed in inflammatory infiltrates.
- Dual checkpoint inhibition correlated with higher cytotoxic T cells and lower macrophages compared to PD1 inhibition alone.
- Responders showed higher CD68+ macrophage and CD11c+ or CD4+ T cell abundance in rash compared to non-responders.
- The skin microenvironment exhibited epidermal proliferation and thickening.
Conclusions:
- The type of checkpoint inhibitor combination influences skin infiltrate composition.
- Specific immune cell abundances in cutaneous eruptions correlate with patient response to checkpoint inhibitor therapy.
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