Increased natural killer cells and decreased regulatory T cells are seen in complex atypical endometrial hyperplasia and well-differentiated carcinoma treated with progestins
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Abstract
Progestins are used to treat complex atypical hyperplasia and well-differentiated
endometrial carcinoma in women who desire fertility preservation and those who are
poor surgical candidates. Although sensitivity to progestins is thought to be associated
with the presence of estrogen and progesterone receptors, it is known that receptor-negative
tumors can also respond to the agent, suggesting that there is another direct antitumor
action of progestin. Because tumor immune response is an additional predictor of survival
in well-differentiated endometrial carcinoma, it is surprising that the role of progestins
in tumor immunity has not been investigated. Regulatory T cells modulate the immune
response, whereas cytotoxic T cells directly target tumor cells. In this study, we
investigated the effect of progestins on regulatory T cells and cytotoxic T cells.
The pre- and posttreatment endometrial samples of 15 progestin-treated patients with
complex atypical hyperplasia or well-differentiated endometrial carcinoma were evaluated
for therapeutic response and the presence of cytotoxic T cells and regulatory T cells.
Immunohistochemical analysis was performed for FOXP3 to identify regulatory T cells
and for granzyme B to identify activated cytotoxic T cells. To further characterize
the cytotoxic T cell's subpopulations, we performed CD8 (cytotoxic T-cell marker)
and CD56 (natural killer cells marker). Ten of 15 patients had normal morphology on
follow-up endometrial samplings, and 4 patients had persistence or progression of
the disease. Regulatory T-cell counts pretreatment were significantly higher in complex
atypical hyperplasia and well-differentiated endometrial carcinoma than in posttreatment
normal endometrium. Residual complex atypical hyperplasia and well-differentiated
endometrial carcinoma present in posttreatment samples maintained high regulatory
T cells and low number of cytotoxic T cells. Progestin treatment was associated with
striking increase in cytotoxic T cells in areas with decidual reaction. Before treatment,
most of the granzyme B+ cytotoxic T cells in complex atypical hyperplasia and well-differentiated
endometrial carcinoma were CD8(+) T cells, whereas after treatment, up to 80% of cytotoxic
T cells were natural killer cells. These results suggest that progestin treatment
affects subpopulations of lymphocytes in the endometrium and may induce immune suppression
of complex atypical hyperplasia and well-differentiated endometrial carcinoma.