論文の公開元へSurvival Analyses Based on Tumor Microenvironment Profile in Endometrial Carcinoma
概要
[Purpose] Tumor microenvironment (TME) including the immune checkpoint system impacts prognosis in some types of malignancy. The aim of our study was to investigate the precise prognostic significance of the TME profile in endometrial carcinoma.
[Materials and methods] We performed immunohistochemistry of the TME proteins, PD-L1, PD-1, CD4, CD8, CD68, and VEGF in endometrial carcinomas from 221 patients who received surgery in the Department of Obstetrics and Gynecology at the University of Tsukuba Hospital between 1999 and 2009.
[Results] High PD-L1 in tumor cells (TCs) was associated with better overall survival (OS) (p = 0.004), whereas high PD-L1 in tumor-infiltrating immune cells (TICs) was associated with worse OS (p = 0.02). High PD-L1 in TICs correlated with high densities of CD8+ TICs and CD68+ TICs, as well as microsatellite instability (MSI) (p = 0.00000064, 0.00078, and 0.0056), while high PD-L1 in TCs correlated with longer treatment-free interval (TFI) after primary chemotherapy in recurrent cases (p = 0.000043). High density of CD4+ TICs correlated with better OS and longer TFI (p = 0.0008 and 0.014). Univariate and multivariate analyses of prognostic factors revealed that high PD-L1 in TCs and high density of CD4+ TICs were significant and independent for favorable OS (p = 0.014 and 0.0025).
[Discussion] High PD-L1 expression in TICs showed an inverse correlation with high PD-L1 expression in TCs, and those expressions exhibited opposite prognostic associations for OS. These observations may be explicable if some proportion of expressed PD-L1 could move between the surface of TCs and the surface of TICs so that the PD-L1 bound to PD-1 on the surface of TICs may induce adaptive immune resistance leading to poor survival, while the PD-L1 remaining on the surface of TCs may not. This hypothesis may be supported by the published findings that, in addition to tissue PD-L1, there also exist circulating PD-L1 such as exosomal PD-L1 and soluble PD-L1. Further molecular and clinical investigations are essential to verify our observation and to elucidate the mechanism underlying them. High PD-L1 expression in TICs was associated with MSI, and with high density of CD8+ TICs and CD68+ TICs, suggesting that PD-L1-induced adaptive immune resistance may involve MSI, killer T cells. MSI is known to cause hypermutation leading to increased burden of tumor antigens, which induces increased immune response. Increased immune response may induce PD-1/PD-L1-mediated adaptive immune resistance, which will lead to aggressive tumor phenotype and poor prognosis. Taken together, these findings suggest that PD-L1 expression of TICs may be a biomarker for the T cell-inflamed tumor phenotype. Clinical response to anti-PD-1 monoclonal antibody was reported to occur almost exclusively in patients with pre-existing T cell infiltrates in the region of PD-L1 upregulation. Following anti-PD-1 administration, these CD8+ T cells seemed to proliferate and expand to penetrate throughout the tumor, which correlated with tumor regression. Altogether, our findings implicate that anti-PD-1/PD-L1 therapy may improve the unfavorable survival of the subset of endometrial cancers with TICs expressing high PD-L1.
Moreover, in the analysis of the associations between the TME protein expressions and TFI after primary adjuvant chemotherapy, high PD-L1 expression in TCs indicated a longer TFI, suggesting that prognostic impact of PD-L1 expression may be mediated by affected chemosensitivity. This hypothesis may be supported by the published findings where upregulation of the PD-1/PD-L1 axis confers chemoresistance in some types of tumor. Accordingly, our findings further suggest that anti-PD-1/PD-L1 therapy may attenuate chemoresistance in the patients with TICs expressing high PD-L1.
In the univariate and multivariate analyses of prognostic factors, high density of CD4+ TICs was also found to be significant and independent for favorable OS. Besides, high density of CD4+ TICs was found to be associated with longer TFI, suggesting that helper T cells also may affect prognosis through involving chemosensitivity.
Our findings indicate that anti-PD1/PD-L1 therapies combined with conventional chemotherapeutics may be beneficial for the patients with poor prognosis due to high PD-L1 expression in TICs through improving chemosensitivity.
[Conclusion] The current findings indicate that PD-L1 and CD4+ helper T cells may be reasonable targets for improving survival through manipulating chemosensitivity, providing significant implications for combining immunotherapies into the therapeutic strategy for endometrial carcinoma. Further studies are warranted to clarify the clinical and prognostic significance of the TME status in endometrial cancer.
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