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Immune-based biomarker accurately predicts response to imiquimod immunotherapy in cervical high-grade squamous
Ziena Abdulrahman1,2, Natasja Hendriks3, Arnold J Kruse3
1Leiden University Medical Center, Leiden, The Netherlands.
Insights
A new biomarker, the cervical high-grade squamous intraepithelial lesion immune biomarker for imiquimod (CIBI), accurately predicts response to imiquimod immunotherapy in cHSIL patients. This biomarker helps avoid unnecessary treatments and adverse effects for non-responders.
Area of Science:
- Immunology
- Oncology
- Biomarker Discovery
Background:
- Cervical high-grade squamous intraepithelial lesion (cHSIL) patients have a ~60% response rate to imiquimod immunotherapy, leading to potential adverse effects in non-responders.
- Standard surgical treatments carry risks, including increased premature birth rates in subsequent pregnancies.
- Identifying predictive biomarkers for imiquimod response is crucial for optimizing treatment efficacy and patient safety.
Purpose of the Study:
- To analyze the cHSIL immune microenvironment to identify a predictive biomarker for imiquimod response.
- To enhance therapeutic efficacy and minimize adverse effects for patients unlikely to respond to imiquimod.
Main Methods:
- Analyzed pre- and post-treatment biopsies from 35 cHSIL patients using multispectral immunofluorescence for T cell and myeloid cell composition.
- Developed a simplified immunohistochemical detection protocol and utilized machine learning for automated cell identification.
- Quantified immune cell populations, including T helper cells, M1-like macrophages, dendritic cells, and regulatory T cells.
Main Results:
- Complete responders (CR) showed pre-treatment infiltration of T helper cells, M1-like macrophages, and dendritic cells, while non-responders (NRs) had high regulatory T cell infiltration.
- Post-treatment, CR patients exhibited increased intraepithelial and stromal CD4+ T cells, unlike NR patients.
- A quantitative biomarker, the CIBI, based on pre-existing immune cell counts, demonstrated excellent predictive capacity (AUC 0.95, p<0.0001).
Conclusions:
- Patient response to imiquimod is linked to a pre-existing local immune response that facilitates increased T cell infiltration.
- The CIBI biomarker shows significant potential for selecting cHSIL patients likely to achieve a complete response to imiquimod immunotherapy.
Background:
The complete response rate of cervical high-grade squamous intraepithelial lesion (cHSIL) patients to imiquimod immunotherapy is approximately 60%. Consequently, many patients are exposed to unnecessary adverse effects of imiquimod. On the other hand, conventional surgical large loop excision therapy is associated with increased risk of premature births in subsequent pregnancies. An in-depth analysis of the cHSIL immune microenvironment was performed in order to identify and develop a predictive biomarker for response to imiquimod, to maximize therapy efficacy and to avoid adverse effects in patients unlikely to respond.
Methods:
Biopsies of 35 cHSIL patients, before and 10 weeks on imiquimod treatment, were analyzed by two multispectral seven-color immunofluorescence panels for T cell and myeloid cell composition in relation to treatment response. Based on these results a simplified immunohistochemical detection protocol was developed. Samples were scanned with the Vectra multispectral imaging system and cells were automatically identified using machine learning.
Results:
The immune microenvironment of complete responders (CR) is characterized by a strong and coordinated infiltration by T helper cells (activated PD1+/type 1 Tbet+), M1-like macrophages (CD68+CD163-) and dendritic cells (CD11c+) prior to imiquimod. The lesions of non-responders (NRs) displayed a high infiltration by CD3+FOXP3+ regulatory T cells. At 10 weeks on imiquimod, a strong influx of intraepithelial and stromal CD4+ T cells was observed in CR but not NR patients. A steep decrease in macrophages occurred both in CR and NR patients, leveling the pre-existing differences in myeloid cell composition between the two groups. Based on the pre-existing immune composition differences, the sum of intraepithelial CD4 T cell, macrophage and dendritic cell counts was used to develop a quantitative simplified one color immunohistochemical biomarker, the CHSIL immune biomarker for imiquimod (CIBI), which can be automatically and unbiasedly quantified and has an excellent predictive capacity (receiver operating characteristic area under the curve 0.95, p<0.0001).
Conclusion:
The capacity of cHSIL patients to respond to imiquimod is associated with a pre-existing coordinated local immune process, fostering an imiquimod-mediated increase in local T cell infiltration. The CIBI immunohistochemical biomarker has strong potential to select cHSIL patients with a high likelihood to experience a complete response to imiquimod immunotherapy.
