This study utilized multispectral immunofluorescence analysis to validate the correlation between pre-existing immune cell infiltration and treatment outcomes for imiquimod in vulvar high-grade squamous intraepithelial lesions (vHSIL). It demonstrated that patients achieving quick complete response (qCR) exhibited higher infiltration levels of CD4+, CD8+ T cells, and CD14+ inflammatory myeloid cells, while slow complete responders (sCR) showed increased CD4+PD1+ T cell infiltration but reduced CD14+ cells. Non-responders (NR) exhibited elevated infiltration of immunosuppressive CD33+ immature cells.
Literature Overview
This article titled 'Pre-existing infiltration with T cells and CD14+ myeloid cells is associated with treatment response to imiquimod in primary and recurrent vulvar high-grade squamous intraepithelial lesions', published in the Journal for Immunotherapy of Cancer, reviews and summarizes the immune microenvironment characteristics of vHSIL patients from the PITVIN prospective randomized controlled trial. By analyzing pre-treatment immune cell infiltration in relation to clinical outcomes, it identifies higher CD4+, CD8+ T cells and CD14+ inflammatory myeloid infiltration in qCR patients, versus increased CD33+ immature cell infiltration in NR cases.
Background Knowledge
vHSIL is a premalignant lesion caused by persistent high-risk human papillomavirus (hrHPV) infection. Traditional treatments include surgical excision or laser ablation, which may lead to anatomical alterations and psychological sexual dysfunction. Imiquimod, a TLR7 agonist, induces local antiviral and antitumor immunity through Th1 activation. Despite its high overall complete response rate (≈80%), some patients require prolonged treatment or surgical intervention. Previous studies suggested immune microenvironment composition as predictive biomarkers, but this study represents the first systematic validation of immune infiltration features across different response types (qCR, sCR, NR) in a prospective trial.
Research Methods and Experiments
The study analyzed pre-treatment formalin-fixed paraffin-embedded (FFPE) tissue samples (n=38) from vHSIL patients in the PITVIN trial using multispectral immunofluorescence staining and Vectra imaging microscopy to characterize T cell and myeloid cell composition. Semi-supervised machine learning was applied for cell phenotyping. Clinical responses were categorized as quick complete response (qCR: lesion-free within 16 weeks), slow complete response (sCR: response achieved after extended treatment to 6 months), and non-response (NR: persistent vHSIL at 6 months requiring surgery or prolonged therapy).
Key Conclusions and Perspectives
Research Significance and Prospects
This study establishes immune microenvironment analysis as a foundation for predicting non-surgical treatment efficacy in vHSIL. Future development of biomarkers targeting T cell and myeloid combinations may optimize personalized therapy. Notably, sCR patients could benefit from combined PD-1/PD-L1 inhibition, though balancing risks of treatment-related adverse events is essential.
Conclusion
This study demonstrates that coordinated infiltration of CD4+ T cells, CD8+ T cells, and CD14+ inflammatory myeloid cells in the pre-treatment immune microenvironment correlates with complete response to imiquimod in vHSIL patients, while delayed or absent responses associate with increased immunosuppressive myeloid cells (e.g., CD33+ MDSC) or lack of coordinated responses. These findings support immunohistochemical assessment of patient immune status in clinical practice to predict imiquimod response and optimize treatment duration. Additionally, the research emphasizes the central role of local immune environments in treatment responses, suggesting future development of immunomarkers to guide personalized therapeutic strategies. Although limited by small sample size and inter-individual variability, this work provides theoretical foundations for precision immune modulation in non-surgical interventions.
