Background Immunosuppressive medication is mandatory in the majority of solid organ transplant recipients to reduce the risk of allograft rejection. An increased risk to develop cancer is a negative side effect of long-term immunosuppression and impaired cancer immunosurveillance is assumed as underlying mechanism. However, the impact of immunosuppression on the tumor immune microenvironment (TME) is poorly understood. In this study we aimed to elucidate differences between immune infiltrates of post-transplant malignancies and cancer of non-immunosuppressed patients.
Materials and Methods 117 resected tumor samples of 80 organ transplant (kidney, heart, lung and liver) recipients were included. Immunohistochemistry and digital image analysis of whole section slides was used to quantify T- (CD3, CD8) and B-cell (CD20) abundance in the TME of 14 different cancer types. These data were used to calculate the Immune-score and to quantify tertiary lymphoid structures in the TME. Expression of Human-Leucocyte-Antigen-I (HLA-I) and programmed cell death ligand 1 (PD-L1) were analyzed in tissue microarrays. Clinical parameters were included in statistical analyses.
Results The increased risk of cancer in organ transplant recipients was reflected by a remarkably reduced immune infiltrate in the central region (CT) and the surrounding tissue (invasive margin, IM) of cancer areas. T cell abundance was decreased in IM and CT of skin (814 vs. 1440 CD3+ cells/mm2, p < 0.01) and non-skin tumors (479 vs. 781 CD3+ cells/mm2, p < 0.01), when compared to non-immunosuppressed controls. These differences were more pronounced in the IM than in the CT and larger when comparing abundance of CD8+ T cells. The Immune-score integrating results from CT and IM was also decreased in transplant recipients. Similar to the results observed for T cells, B cell abundance and density of tertiary lymphoid structures were lower in cancer samples of transplant recipients. Decreased expression of HLA-I was more common in transplant recipients whereas the fraction of samples with PD-L1 expression was higher in controls.
Conclusions Our study demonstrates that post-transplant malignancies show a low immune infiltrate and supports the hypothesis of reduced anti-tumor immune response as an important mechanism underlying increased risk of cancer in organ transplant recipients. Optimized immunosuppressive protocols may be able to reduce cancer incidence and cancer therapies need to consider the distinct immune microenvironment of post-transplant malignancies.
Disclosure Information S. Schran: None. R. Datta: None. O. Persa: None. C. Aguilar: None. M. Thelen: None. J. Lehmann: None. M. Garcia-Marquez: None. K. Wennhold: None. A. Quaas: None. C. Bruns: None. C. Mauch: None. H. Löser: None. D. Stippel: None. H. Schlößer: None.
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