Introduction/Background Achieving positive outcomes of using immunotherapeutic approaches in cancer treatment implies multifaceted targeting of functionally different mechanisms of immune response, including mechanisms governed by molecules of immune checkpoint system. Functional roles of immune checkpoints in different immune cell subsets of cancer patients are not comprehensively characterized; the existing data are sometimes controversial. Studying the immune checkpoint expression patterns in initial stages of invasive tumor growth and progression, in comparison with non-invasive neoplastic lesions, may help better understand their involvement in regulating tumor-immunity interactions. Little or virtually no data are available for very early (preclinical) cervical cancer.
Methodology Fresh cervical epithelial tissue specimens (along with peripheral blood) were collected from women with preclinical early invasive and non-invasive squamous carcinoma of the cervix. Cell suspensions obtained by gentle enzymatic dissociation were subjected to multicolor flow cytometry. Co- expression of PD-1/CD279, PD-L1/CD274, TIM-3/CD366, and LAG-3/CD223 markers was evaluated in major populations of tumor-infiltrating CD4 and CD8 T lymphocytes, including their regulatory subset (Treg), and compared to circulating T cells.
Results PD-1/-L1, TIM-3 and LAG-3 were analyzed in total CD4/CD8 T cells, CD4/8CD25(±) T subsets, and CD4/8CD25(+/high)CD127(-/low) Treg. Tumor-infiltrating (TILs) and peripheral blood (PBLs) lymphocytes, either CD4 or CD8, were shown to have different expression levels of immune checkpoint markers with significantly higher levels found on TILs. Early invasive and non-invasive carcinoma samples could also be stratified according to the frequencies of TILs. TIM-3 and LAG-3 were strongly co-expressed with PD-1/-L1 on TILs. The prevalence of CD25(+/high)CD127(-/low) cells among CD4 (CD8) TILs was significantly higher than among PBLs with the highest difference observed for CD8 subset, and the majority of these cells co-expressed PD-1 with TIM-3/LAG-3. All analyzed TILs subsets were found to have exclusively high levels of PD-L1.
Conclusion The findings indicate deep involvement of immune checkpoint mechanisms in initiation of invasive growth of cervical carcinoma.
Disclosure The work is supported by the Russian Science Foundation (grant No.17-15-01024).
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