In the tumor microenvironment, metabolic reprogramming can impact metabolic characteristics of T cells, thus inducing immunosuppression to promote tumor immune escape. The mammalian target of rapamycin (mTOR) signaling pathway plays an important role in regulating diverse functions of various immune cells. This review mainly focuses on the molecular mechanism of mTOR signaling in regulating cellular energy metabolism process, and the activation status of mTOR signaling under different nutritional environments. In addition, it also summarizes the role of the mTOR signaling in regulatory T cell (Tregs) metabolism and function in current studies, and evaluates the potential of mTOR as a clinical immunotherapeutic target and its current application challenges.
Immunosuppression Therapy ; Metabolic Reprogramming ; Signal Transduction ; Sirolimus ; T-Lymphocytes, Regulatory ; TOR Serine-Threonine Kinases ; Humans

Tumor progression is closely related to tumor tissue metabolism and reshaping of the microenvironment. Oral squamous cell carcinoma (OSCC), a representative hypoxic tumor, has a heterogeneous internal metabolic environment. To clarify the relationship between different metabolic regions and the tumor immune microenvironment (TME) in OSCC, Single cell (SC) and spatial transcriptomics (ST) sequencing of OSCC tissues were performed. The proportion of TME in the ST data was obtained through SPOTlight deconvolution using SC and GSE103322 data. The metabolic activity of each spot was calculated using scMetabolism, and k-means clustering was used to classify all spots into hyper-, normal-, or hypometabolic regions. CD4T cell infiltration and TGF-β expression is higher in the hypermetabolic regions than in the others. Through CellPhoneDB and NicheNet cell-cell communication analysis, it was found that in the hypermetabolic region, fibroblasts can utilize the lactate produced by glycolysis of epithelial cells to transform into inflammatory cancer-associated fibroblasts (iCAFs), and the increased expression of HIF1A in iCAFs promotes the transcriptional expression of CXCL12. The secretion of CXCL12 recruits regulatory T cells (Tregs), leading to Treg infiltration and increased TGF-β secretion in the microenvironment and promotes the formation of a tumor immunosuppressive microenvironment. This study delineates the coordinate work axis of epithelial cells-iCAFs-Tregs in OSCC using SC, ST and TCGA bulk data, and highlights potential targets for therapy.
Humans ; Carcinoma, Squamous Cell/metabolism* ; Squamous Cell Carcinoma of Head and Neck ; Mouth Neoplasms/metabolism* ; Immunosuppression Therapy ; Transforming Growth Factor beta ; Head and Neck Neoplasms ; Gene Expression Profiling ; Tumor Microenvironment

Collapsing Glomerulopathy (CG) is a rare entity presenting as nephrotic syndrome and rapidly progressive renal deterioration. It has been first identified among African-American patients and subsequently dubbed HIV-associated nephropathy after a number of patients with HIV were found to have CG. It has re-emerged recently among patients with COVID-19. To our knowledge, this is the first case of primary collapsing glomerulopathy in the country to be published. The case is a 36-year-old Filipino female admitted due to bipedal edema which started 2 weeks post-partum. She has no comorbidities and social history was negative for illicit drug use. Initial work up showed hypoalbuminemia and diffuse hepatic disease on ultrasound. She was referred to a gastroenterologist where albumin infusion and paracentesis was done but with no improvement. She developed anasarca and was admitted. Paracentesis obtained minimal ascitic fluid. Serum ascites albumin gradient was low and baseline laboratories showed high creatinine, hypoalbuminemia, and albuminuria. 24-hour urine protein was 11 grams, ANA and anti-DsDNA were negative and c3 and c4 levels were normal. Hepatitis profile was negative for infection. Abdominal CT scan revealed multiple hypoenhancing lesions. Tumor markers CA-125, CA 19-9 and CA 15-3 were high. Breast ultrasound showed simple breast cyst. Gynecology consult was called where pap smear was negative for atypical cells. Surgery service recommended monitoring for the pancreatic and breast lesions. Kidney biopsy was delayed due to new onset bacterial pneumonia. COVID-19 RT-PCR test was negative. Patient was discharged improved with no edema. On follow up, the kidney biopsy result came out to be collapsing glomerulopathy. HIV test was then done and was negative. Bipedal edema and albuminuria recurred. She was started on tacrolimus. She has been on regular follow up and currently has no edema, no proteinuria and normal creatinine level. This is an interesting case as the primary glomerular disease has been masked by the earlier laboratory findings which led us to think of liver disease then a paraneoplastic nephrotic syndrome. Ultimately, the renal biopsy revealed the diagnosis. This serves as an index case for primary collapsing glomerulopathy in a Filipino patient on remission after being treated with tacrolimus.
Nephrotic Syndrome ; Immunosuppression Therapy

We present a case of Nannizziopsis spp infection in an immunocompromised patient, describe clinical findings, investigation results and treatment. This rare fungal infection is reported in reptiles and humans, but not other mammals. There are only twenty case reports in medical literature to date, most in immunocompromised patients.

A 64-year-old kidney transplant recipient from urban Nigeria presented with a verrucous plaque on his dorsal left hand which has grown rapidly over the two months. He was concerned that it might represent cancer. On further examination he also had a subcutaneous fluctuant masses on his left flank and left upper arm, a fleshy mucosal plaque and a large tender fluctuant swelling over his right tibia. He was clinically well, but in the preceding months he reported haemoptysis and 7 kilograms weight loss.

Skin biopsies from multiple sites showed identical features: suppurative granulomatous inflammation and elongated elements consistent with fungal hyphae. Grocott special staining showed scattered fungal hyphae. Beta-D-glucan was raised at 441.4 pg/mL [3-6 pg/mL]. Subsequent molecular identification confirmed Nanniziopsis spp, likely to be N. guarroi. He was treated with intravenous amphotericin-B for 7 weeks and was then switched to oral posaconazole for one month with complete resolution.

Nannizziopsis is an emerging human pathogenic fungus that predominantly causes disease in immunocompromised individuals. This case highlights the importance of suspecting atypical fungal infection in immunocompromised individuals presenting with polymorphic skin lesions and the critical diagnostic role of skin biopsy and culture.

The multiple myeloma (MM), the second most common hematologic malignancy, is malignant proliferative disease of plasma cells. Although the application of many targeted drugs has significantly prolonged the survival time of MM patients, it is still an incurable disease. In recent years, the immunosuppression caused by interaction between tumor microenvironment(TME) and tumor cells has attracted people's attention gradually. As a kind of immunosuppressive cells in TME, regulatory T cells (Treg) play an important role in the progress of MM. Treg is related to the proliferation and metastasis of tumors, and can lead to the progress of MM by promoting the angiogenesis and generating immunosuppressive TME. In this review, we briefly summarized the latest research progress on the impact of Treg on the pathogenesis of MM.
Humans ; Multiple Myeloma/pathology* ; T-Lymphocytes, Regulatory/pathology* ; Immune Tolerance ; Plasma Cells/pathology* ; Immunosuppression Therapy ; Tumor Microenvironment

Objectives Objectives To investigate how the imbalance of innate lymphoid cells (ILCs)in the peripheral blood of patients with lung adenocarcinoma affects the balance of downstream mononuclear macrophages and T helper (Th) cells, and to identify the impact of the imbalance of ILCs on the immune status and prognosis of lung adenocarcinoma. Methods The peripheral blood of 20 patients with lung adenocarcinoma and normal controls were collected. The percentage of ILCs, mononuclear macrophages and T lymphocyte in peripheral blood were analyzed by flow cytometry. The characteristic cytokine secretion levels of various types of immune cells in peripheral blood were detected by real-time fluorescence quantitative PCR. Results Compared with the normal controls, the proportion of M2 mononuclear macrophages, ILC1 and ILC2 in patients with lung adenocarcinoma was up-regulated, while the proportion of M1 mononuclear macrophages, CD4⁺ T and CD8⁺ T was down-regulated. The mRNA expression of related cytokines of M1 mononuclear macrophages and ILC1 were decreased; while the mRNA expression of related cytokines of M2 mononuclear macrophages and ILC2 were increased. Along with the decreased CD4⁺T cells-associated cytokine T-bet mRNA expression, and the increased GATA3 mRNA expression. Moreover, the expression of PD-1 in CD8⁺ T cells was also up-regulated. Conclusion The imbalance of ILCs in peripheral blood of patients with lung adenocarcinoma promotes the imbalance of mononuclear macrophages and Th cells, which altogether maintains the immunosuppression in patients with lung adenocarcinoma, and promotes the development of lung adenocarcinoma.
Humans ; Lymphocytes ; Immunity, Innate ; CD8-Positive T-Lymphocytes ; Cytokines/metabolism* ; Adenocarcinoma of Lung ; Immunosuppression Therapy ; RNA, Messenger

A complex pathophysiological mechanism is involved in brain injury following cerebral infarction. The neurovascular unit (NVU) is a complex multi-cellular structure consisting of neurons, endothelial cells, pericyte, astrocyte, microglia and extracellular matrix, etc. The dyshomeostasis of NVU directly participates in the regulation of inflammatory immune process. The components of NVU promote inflammatory overreaction and synergize with the overactivation of autonomic nervous system to initiate stroke-induced immunodepression (SIID). SIID can alleviate the damage caused by inflammation, however, it also makes stroke patients more susceptible to infection, leading to systemic damage. This article reviews the mechanism of SIID and the roles of NVU in SIID, to provide a perspective for reperfusion, prognosis and immunomodulatory therapy of cerebral infarction.
Humans ; Endothelial Cells ; Stroke ; Neurons/physiology* ; Immunosuppression Therapy/adverse effects* ; Cerebral Infarction

Objective: To explore the efficacy of immunosuppression intensified conditioning regimen in patients who have strongly positive donor-specific Anti-HLA antibodies (DSAs) and received a haploidentical hematopoietic stem cell transplantation (haplo-HSCT) . Methods: Clinical data of 10 patients with strongly positive pretransplant DSAs (defined as MFI ≥10000) were retrospectively analyzed in this study. All of them received a haplo-HSCT in the Hematology Department of Shanghai Zhaxin Traditional Chinese & Western Medicine Hospital. Results: ① Of all ten patients, three were males, and seven were females, with a median age of 53.5 (36-64) years. Of the 10 patients, three were diagnosed with acute myeloid leukemia, two were myelodysplastic syndromes (MDS), two were chronic myelomonocytic leukemia (CMML), two were in an accelerated phase of chronic myeloid leukemia (CML-AP), and one was primary myelofibrosis (PMF). ② Conditioning regimen consisted of fludarabine (Flu) /busulfan (Bu) combined with whole-body irradiation (TBI) /cyclophosphamide (Cy). ③ On the seventh day after transplantation, the median pretransplant DSA level was MFI 15 999 (10 210-23 417) and 10 787 (0-22 720). ④ Eight patients acquired hematopoietic reconstitution; the median time of neutrophil engraftment was 14 (10-16) days; and 18 (14-20) days for platelet engraftment. After a median follow-up of 12.5 (1.5-27) months, primary graft failure was found in one patient and another with poor graft function. Seven patients remained in a disease remission state, and all were DSA-negative. Conclusions: An intensified immunosuppression conditioning regimen can efficiently decrease the level of donor-specific anti-HLA antibodies (DSAs), leading to good short-term efficacy.
Male ; Female ; Humans ; Middle Aged ; Retrospective Studies ; Graft vs Host Disease ; Transplantation Conditioning ; China ; Hematopoietic Stem Cell Transplantation ; Antilymphocyte Serum ; Busulfan ; Cyclophosphamide/therapeutic use* ; Immunosuppression Therapy

Objective: To investigate the clinical features of coronavirus disease 2019 (COVID-19) in patients with aplastic anemia (AA) undergoing immunosuppressive therapy (IST) . Methods: In this prospective cohort study, we collected the demographic and clinical data of patients with AA and COVID-19 from December 1, 2022, to January 31, 2023. We described the clinical features of COVID-19 among patients with AA and evaluated the effects of IST on the signs and severity of COVID-19. Results: A total of 170 patients with AA and COVID-19 were included. The common early symptoms, including fever, dizziness or headache, muscle or body aches, and sore throat, disappeared within 1-2 weeks. Approximately 25% of the patients had persistent fatigue within 2 weeks. Many patients experienced cough after an initial 1-3 days of infection, which lasted for more than 2 weeks. There were no differences in the duration of total fever episodes and maximum body temperature when patients were stratified according to whether or not they underwent IST, by IST duration, or by use of anti-lymphocyte globulin (ALG) (P>0.05). No differences were observed in the occurrence of symptoms in either the early or recovery stages when patients with AA were stratified according to whether or not they underwent IST, or by IST duration (P>0.05). However, patients who received ALG had fewer fever episodes within 1 week after infection (P=0.035) and more sore throat episodes within 2 weeks after infection (P=0.015). There were no other significant differences in clinical symptoms between patients who did and patients who did not receive ALG (P>0.05) . Conclusion: The majority of patients with AA and COVID-19 recovered within 2 weeks of noticing symptoms when treated with IST.
Humans ; Anemia, Aplastic ; COVID-19 ; Prospective Studies ; Fever ; Immunosuppression Therapy ; Pharyngitis

Humans ; SARS-CoV-2 ; COVID-19 ; Reverse Transcriptase Polymerase Chain Reaction ; Immunosuppression Therapy ; COVID-19 Testing