[Undistinguishable Cryptococcus-related granulomatous lesion from carcinoma in the tail of the pancreas: a case report].

Abdominal computed tomography revealed a 19×13mm delayed enhancing mass and dilation of the distal pancreatic duct in the head of the pancreas. Magnetic resonance cholangiopancreatography showed pancreatic duct stenosis in the tail of the pancreas. Endoscopic retrograde pancreatography revealed an abrupt interruption of the main pancreatic duct at the tail of the pancreas. We could not assess the distal side of the pancreatic stenosis due to the large extent of obstruction. The pancreatic head mass was diagnosed as adenocarcinoma using endoscopic ultrasound-fine needle aspiration biopsy. However, we could not determine whether the pancreatic duct stenosis in the tail of the pancreas was malignant. Nevertheless, we performed a total pancreatectomy with splenectomy. Histological examination showed poorly differentiated adenocarcinoma in the pancreatic head mass but the pancreatic duct stenosis in the tail of the pancreas was diagnosed as pancreatic granuloma caused by Cryptococcus. Fungal infections may reportedly promote the development of pancreatic cancer, as further suggested by this case of cryptococcal infection.

Relationship between T cell receptor clonotype and PD-1 expression of tumor-infiltrating lymphocytes in colorectal cancer.

Adoptive T cell therapy using tumor-specific T cells or TCR-modified T cells is a promising next-generation immunotherapy. The major source of tumor-reactive T cells is PD-1+ tumor-infiltrating lymphocytes (TILs). In contrast, PD-1- TILs have received little attention. Here, we analyzed the TCR-ß repertoires of PD-1- and PD-1+ CD8+ TILs derived from colorectal cancer and breast cancer. Approximately 40-60% of the PD-1+ population consisted of oligoclonal populations in both colorectal cancer and breast cancer. In contrast, approximately 37% of the PD-1- population consisted of an oligoclonal population in colorectal cancer, whereas 14% of them were oligoclonal in breast cancer. In colorectal cancer, the TCR repertoires of PD-1- CD8+ TILs and PD-1+ CD8+ TILs hardly overlapped. Interestingly, clonally expanded CD8+ TILs in primary tumors and the metastases expressing the same clonotypic TCR showed the same phenotype regarding the PD-1-expression. These results suggest that the intrinsic properties of TCRs determine the fate of TILs in terms of whether they become PD-1+ or PD-1- in the tumor microenvironment. Further functional analysis of TCRs in TILs will allow us to better understand the regulatory mechanisms for PD-1 expression on TILs and may contribute to tumor immunotherapy.

Analysis of TCR Repertoire and PD-1 Expression in Decidual and Peripheral CD8+ T Cells Reveals Distinct Immune Mechanisms in Miscarriage and Preeclampsia.

CD8+ T cells, the most abundant T cell subset in the decidua, play a critical role in the maintenance of pregnancy. The majority of decidual CD8+ T cells have an effector memory phenotype, while those in the peripheral blood display a naive phenotype. An increased amount of highly differentiated CD8+ T cells in the decidua indicates local antigen stimulation and expansion, albeit these CD8+ T cells are suppressed. In decidual CD8+ T cells, co-inhibitory molecules such as PD-1, TIM-3, LAG-3, and CTLA-4 are upregulated, reflecting the suppression of cytotoxicity. Previous studies established the importance of the PD-1/PD-L1 interaction for feto-maternal tolerance. CD8+ T cells could directly recognize fetal-specific antigens, such as HLA-C, expressed by trophoblasts. However, although fetal-specific CD8+ T cells have been reported, their TCR repertoires have not been identified. In this study, we analyzed the TCR repertoires of effector memory CD8+ T cells (CD8+ EM cells) and naive CD8+ T cells (CD8+ N cells) in the decidua and peripheral blood of women with normal or complicated pregnancy and examined PD-1 expression at a single-cell level to verify whether antigen-specific CD8+ T cells accumulate in the decidua and to identify immunological differences related to the suppression of antigen-specific CD8+ T cells between normal pregnancy, miscarriage, and preeclampsia. We observed that some TCRß repertoires, which might recognize fetal or placental antigens, were clonally expanded. The population size of clonally expanded CD8+ EM cells was higher in the decidua than in the peripheral blood. CD8+ EM cells began to express PD-1 during the course of normal pregnancy. We found that the total proportion of decidual CD8+ EM cells not expressing PD-1 was increased both in miscarriage and in preeclampsia cases, although a different mechanism was responsible for this increase. The amount of cytotoxic CD8+ EM cells increased in cases of miscarriage, whereas the expression of PD-1 in clonally expanded CD8+ EM cells was downregulated in preeclampsia cases. These results demonstrated that decidual CD8+ EM cells were able to recognize fetal-specific antigens at the feto-maternal interface and could easily induce fetal rejection.

Clonally Expanded Decidual Effector Regulatory T Cells Increase in Late Gestation of Normal Pregnancy, but Not in Preeclampsia, in Humans.

Background: Regulatory T (Treg) cells are necessary for the maintenance of allogenic pregnancy. However, the repertoire of effector Treg cells at the feto-maternal interface in human pregnancy remains unknown. Our objective was to study T cell receptor (TCR) repertoires of Treg cells during pregnancy compared to normal and complicated pregnancies. Methods:Paired samples of peripheral blood and decidua in induced abortion and miscarriage cases were obtained from consenting patients. CD4+CD25+CD127low/-CD45RA- effector Treg cells were single-cell sorted from mononuclear cells. cDNAs of complementarity determining region 3 (CDR3) in TCRß were amplified from the single cells by RT-PCR and the sequences were analyzed. The TCRß repertoires were determined by amino acid and nucleotide sequences. Treg cells were classified into clonally expanded and non-expanded populations by CDR3 sequences. Results: We enrolled nine induced abortion cases in the 1st trimester, 12 cases delivered without complications in the 3rd trimester, 11 miscarriages with abnormal chromosomal karyotyped embryo, seven miscarriages with normal chromosomal karyotyped embryo, and seven cases of preeclampsia [median gestational week (interquartile range): 7 (7-9), 39 (38-40), 9 (8-10), 8 (8-10), and 34 (32-37), respectively]. The frequency of clonally expanded populations of effector Treg cells increased in decidua of 3rd trimester cases compared to 1st trimester cases [4.5% (1.4-10.8%) vs. 20.9% (15.4-28.1%), p < 0.001]. Clonally expanded Treg cells were rarely seen in peripheral blood. The ratio of clonally expanded populations of decidual effector Treg cells in miscarriages with abnormal and normal embryos was not significantly different compared with that in 1st trimester normal pregnancy. Interestingly, clonally expanded populations of effector Treg cells decreased in preeclampsia compared with that in 3rd trimester normal pregnancy [9.3% (4.4-14.5%) vs. 20.9% (15.4-28.1%), p = 0.003]. When repertoires in previous pregnancy and subsequent pregnancy were compared, some portions of the repertoire were shared. Conclusion: TCR repertoires of decidual effector Treg cells are skewed in the 3rd trimester of normal pregnancy. Failure of clonal expansion of populations of decidual effector Treg cells might be related to the development of preeclampsia.