Immune Microenvironment Characteristics of Urachal Carcinoma and Its Implications for Prognosis and Immunotherapy.

Abstract

Simple SummaryUrachal carcinoma (UrC) is an exceedingly rare tumor and lacks effective treatment. Our study had some important suggestions for targeting programmed cell death-1 (PD-1)/programmed cell death-Ligand 1 (PD-L1) checkpoint in UrC. We fully analyzed the immune microenvironment including intratumoral and peritumoral immune cells, and most of immune cells exerted an immunosuppressive effect; how to reinvigorate immune cells to prevent tumor development would become an important strategy for the treatment of UrC. Tumors with high CD8+ T cell densities also had increasing proportion of PD1 and PD-L1 expression on immune cells, suggesting these partial patients may have developed an activate adaptive immune resistance that might be reversed by treatment of anti-PD-1/PD-L1. No significant difference was found between PD-L1 expression, Mayo stages, and histological type, manifesting that checkpoint inhibitors might be effective for tumors of both early and late stages, as well as with different histological types. Interestingly, we found that the average number of tertiary lymphoid structures (TLS) per slide tended to be higher in tumors with deficient mismatch repair (dMMR) that are promising candidates for immunotherapy, and tumors with higher number of TLS tended to have longer OS and DFS. Increasing CD8+ T cell density was significantly associated with increasing proportion of PD-L1 and PD1 expression on immune cells, and tumors with PD-L1 positive expression on immune cells had significantly increasing proportion of PD1 expression. High peritumoral CD8+ T cell density (>73.7/mm2) was significantly associated with worse OS and DFS. Therefore, the number of TLS seems to be considered not only as histopathological characteristics in predicting MMR status of UrC, but also as the prognostic or therapeutic biomarker, and we also provide some important suggestions for targeting PD-1/PD-L1 checkpoint in UrC. UrC immunosuppressive microenvironment would provide deeper understanding between immune cells, in particular CD8+ T cells, and immunosuppression, thereby facilitating discovery of more rational immunotherapeutic strategies.Urachal carcinoma (UrC) is an exceedingly rare tumor and lacks effective treatment. Herein, we characterized an immune microenvironment characteristic of UrC in detail and identified its implications for prognosis and immunotherapy. In total, 37 resections of UrC were stained for CD20, CD3, CD4, CD8, FOXP3, CD68, HLA-DR, CD163, PD1, and PD-L1, as well as mismatch repair protein including MSH2, MSH6, MLH1, and PMS2 by immunohistochemistry. Intratumoral and peritumoral immune cell densities or the proportion of PD1 and PD-L1 expression alongside MSH2, MSH6, MLH1, and PMS2 status were manually evaluated using the whole slide. UrC patients with the number of tertiary lymphoid structures (TLS) per slide tended to be higher in tumors with dMMR (p = 0.1919), and tumors with higher number of TLS tended to have longer OS (p = 0.0940) and DFS (p = 0.0700). High densities of CD3+ T, CD8+ T, and CD68+ cells were significantly associated with worse OS and DFS (both p<0.05). Increased intratumoral (p = 0.0111) and peritumoral (p = 0.0485) CD8+ T cell densities were significantly associated with PD-L1 expression or increasing proportion of PD-L1 expression on immune cells. Similarly, increased intratumoral (p = 0.0008) and peritumoral (p = 0.063) CD8+ T cell densities were significantly associated with increasing proportion of PD1 expression on immune cells. Tumors with PD-L1 positive expression on immune cells had a significantly increased proportion of PD1 expression (p = 0.0121). High peritumoral CD8+ T cell density (>73.7/mm2) was significantly associated with worse OS (p = 0.0120) and DFS (p = 0.00095). The number of TLS seems to be considered not only as histopathological characteristics in predicting MMR status of UrC, but also as a prognostic or therapeutic biomarker, and we also provide some important suggestions for targeting PD-1/PD-L1 checkpoint in UrC.