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Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
Published on: April 22, 2019
Prospective longitudinal study of immune checkpoint molecule (ICM) expression in immune cell subsets during curative
Adrian von Witzleben1,2,3, Adrian Fehn1, Ayla Grages1
1Department of Otorhinolaryngology and Head & Neck Surgery, University Medical Center Ulm, Head and Neck Cancer Center of the Comprehensive Cancer Center Ulm, Ulm, Germany.
Abstract:
Programmed-death-1 (PD1) antibodies are approved for recurrent and metastatic head and neck squamous cell carcinoma. Multiple drugs targeting costimulatory and coinhibitory immune checkpoint molecules (ICM) have been discovered. However, it remains unknown how these ICM are affected by curative conventional therapy on different immune cell subsets during the course of treatment. In the prospective noninterventional clinical study titled "Immune Response Evaluation to Curative conventional Therapy" (NCT03053661), 22 patients were prospectively enrolled. Blood samples were drawn at defined time points throughout curative conventional treatment and follow-up. Immune cells (IC) from the different time points were assessed by multicolor flow cytometry. The following ICM were measured by flow cytometry: PD1, CTLA4, BTLA, CD137, CD27, GITR, OX40, LAG3 and TIM3. Dynamics of ICM expression were assessed using nonparametric paired samples tests. Significant changes were noted for PD1, BTLA and CD27 on multiple IC types during or after radiotherapy. Nonsignificant trends for increased expression of OX40 and GITR from baseline until the end of RT were observed on CD4 T cells and CD4+ CD39+ T cells. In patients with samples at recurrence of disease, a nonsignificant increase of TIM3 and LAG3 positive CD4+ CD39+ T cells was evident, accompanied by an increase of double positive cells for TIM3/LAG3. Potential future targets to be combined with RT in the conventional treatment and anti-PD1/PD-L could be BTLA agonists, or agonistic antibodies to costimulatory ICM like CD137, OX40 or GITR. The combination of cetuximab with CD27 agonistic antibodies enhancing ADCC or the targeting of TIM3/LAG3 may be another promising strategy.
Insights
Curative conventional therapy significantly alters immune checkpoint molecules (ICM) like PD1, BTLA, and CD27 on immune cells. This study reveals how these changes impact treatment response and suggests novel combination therapies for head and neck squamous cell carcinoma.
Area of Science:
- Immunology
- Oncology
- Cancer Therapy
Background:
- Immune checkpoint molecules (ICM) are crucial targets for cancer immunotherapy, particularly in head and neck squamous cell carcinoma (HNSCC).
- The impact of curative conventional therapy on ICM expression across various immune cell subsets remains largely unexplored.
- Understanding these dynamics is vital for developing effective combination treatment strategies.
Purpose of the Study:
- To investigate the dynamic changes in ICM expression on immune cells during and after curative conventional therapy in HNSCC patients.
- To identify specific ICM that are significantly modulated by radiotherapy and other conventional treatments.
- To explore potential novel therapeutic targets based on observed ICM expression patterns.
Main Methods:
- Prospective enrollment of 22 HNSCC patients undergoing curative conventional therapy.
- Collection of blood samples at multiple time points during treatment and follow-up.
- Multicolor flow cytometry analysis to quantify expression of PD1, CTLA4, BTLA, CD137, CD27, GITR, OX40, LAG3, and TIM3 on various immune cell subsets.
Main Results:
- Significant alterations in PD1, BTLA, and CD27 expression were observed on multiple immune cell types during or after radiotherapy.
- Trends towards increased OX40 and GITR expression were noted on CD4 T cells and CD4+CD39+ T cells.
- In patients with disease recurrence, a non-significant increase in TIM3 and LAG3 expression on CD4+CD39+ T cells was observed.
Conclusions:
- Curative conventional therapy induces significant changes in immune checkpoint molecule expression on immune cells.
- Modulated ICM present potential targets for combination therapies with anti-PD1/PD-L1 agents.
- Strategies involving BTLA agonists, costimulatory ICM agonists (CD137, OX40, GITR), or targeting TIM3/LAG3 warrant further investigation for HNSCC treatment.
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