Modification Of Immunosuppression Research Articles

Engineering mesoporous polydopamine-based potentiate STING pathway activation for advanced anti-biofilm therapy

The biofilm-induced “relatively immune-compromised zone” creates an immunosuppressive microenvironment that is a significant contributor to refractory infections in orthopedic endophytes. Consequently, the manipulation of immune cells to co-inhibit or co-activate signaling represents a crucial strategy for the management of biofilm. This study reports the incorporation of Mn2+ into mesoporous dopamine nanoparticles (Mnp) containing the stimulator of interferon genes (STING) pathway activator cGAMP (Mncp), and outer wrapping by M1-like macrophage cell membrane (m-Mncp). The cell membrane enhances the material's targeting ability for biofilm, allowing it to accumulate locally at the infectious focus. Furthermore, m-Mncp mechanically disrupts the biofilm through photothermal therapy and induces antigen exposure through photodynamic therapy-generated reactive oxygen species (ROS). Importantly, the modulation of immunosuppression and immune activation results in the augmentation of antigen-presenting cells (APCs) and the commencement of antigen presentation, thereby inducing biofilm-specific humoral immunity and memory responses. Additionally, this approach effectively suppresses the activation of myeloid-derived suppressor cells (MDSCs) while simultaneously boosting the activity of T cells. Our study showcases the efficacy of utilizing m-Mncp immunotherapy in conjunction with photothermal and photodynamic therapy to effectively mitigate residual and recurrent infections following the extraction of infected implants. As such, this research presents a viable alternative to traditional antibiotic treatments for biofilm that are challenging to manage.

Exosomes derived from cord blood Treg cells promote diabetic wound healing by targeting monocytes

Chronic nonhealing diabetic wounds are a critical clinical challenge. Regulatory T cells (Tregs) are immunosuppressive modulators affecting wound healing progression by controlling the inflammatory response. The current study attempted to investigate whether the exosomes derived from cord blood (CB) Tregs can accelerate the healing process. Exosomes were isolated from CB-Treg cultures using ultracentrifugation and validated with different specific markers of exosomes. The purified CB-Treg-derived exosomes were co-cultured with peripheral blood mononuclear cells (PBMCs) and CD14+ monocytes. The migration-promoting effect of CB-Treg-derived exosomes on fibroblasts and endothelial cells was investigated. We used thermosensitive Pluronic F-127 hydrogel (PF-127) loaded with CB-Treg-derived exosomes in a diabetic wound healing mouse model. CB-Treg-derived exosomes with 30–120 nm diameters revealed exosome-specific markers, such as TSG101, Alix, and CD63. CB-Treg-derived exosomes were mainly bound to the monocytes when co-cultured with PBMCs, and promoted monocyte polarization to the anti-inflammatory phenotype (M2) in vitro. CB-Treg-derived exosomes enhanced the migration of endothelial cells and fibroblasts. Furthermore, CB-Treg-derived exosomes treatment accelerated wound healing by downregulating inflammatory factor levels and upregulating the M2 macrophage ratio in vivo. Our findings indicated that CB-Treg-derived exosomes could be a promising cell-free therapeutic strategy for diabetic wound healing, partly by targeting monocytes.

Modulation of cyclophosphamide-induced immunosuppression and intestinal flora in broiler by deep eutectic solvent extracted polysaccharides of Acanthopanax senticosus.

The aim of this experiment was to investigate the modulation effect of Acanthopanax senticosus polysaccharide (ASPS-PD) extracted with deep eutectic solvent on cyclophosphamide-induced immunosuppression in broilers and its modulation of the gut microbiota of broilers. The 108 one-day-old broilers were divided into six groups, including the control group, the Cyclophosphamide (CY) model group, the ASPS-PD control group, the ASPA-PD high and low dose groups and the Astragalus polysaccharide group. Body weight, feed intake, feed conversion ratio, and immune organ index of broilers at 7, 14, and 21 days were determined; IL-2, IFN-γ, and lgG1 levels were determined by enzyme-linked immunosorbent assay (ELISA); Broiler caeca feces were analyzed by amplification and 16S rRNA sequencing. The results showed that ASPS-PD can restore growth performance, increase immune organ index and improve serum cytokine levels of IL-2 and IFN-γ and immunoglobulin lgG1 levels in CY-treated broilers. The analysis of cecum flora showed that ASPS-PD can promote the proliferation of beneficial bacteria and reduce the number of harmful bacteria, regulating intestinal flora. Therefore, ASPA-PD may be a potential novel immunomodulator to ameliorate CY-induced immunosuppression and intestinal flora dysregulation in broiler.

The value of extracorporeal photopheresis as an immunosuppression-modifying approach in solid organ transplantation: a potential solution to an unmet medical need

Allograft rejection is a critical issue following solid organ transplantation (SOT). Immunosuppressive therapies are crucial in reducing risk of rejection yet are accompanied by several significant side effects, including infection, malignancy, cardiovascular diseases, and nephrotoxicity. There is a current unmet medical need with a lack of effective minimization strategies for these side effects. Extracorporeal photopheresis (ECP) has shown potential as an immunosuppression (IS)-modifying technique in several SOT types, with improvements seen in acute and recurrent rejection, allograft survival, and associated side effects, and could fulfil this unmet need. Through a review of the available literature detailing key areas in which ECP may benefit patients, this review highlights the IS-modifying potential of ECP in the four most common SOT procedures (heart, lung, kidney, and liver transplantation) and highlights existing gaps in data. Current evidence supports the use of ECP for IS modification following SOT, however there is a need for further high-quality research, in particular randomized control trials, in this area.

Azathioprine Associated with Intrahepatic Cholestasis in a Patient with Twin Pregnancy after a Second Kidney Transplant.

Most pregnancies in women after a kidney transplant result in a live birth, but kidney functions should be stable for one year before conception. For immunosuppression modification occurring before pregnancy, azathioprine is used because it is considered safe for major congenital malformations during pregnancy. However, there may be an association between exposure to azathioprine during pregnancy and the onset of an unusual, early and severe form of intrahepatic cholestasis. A young patient with a twin pregnancy after a second kidney transplant experienced intrahepatic cholestasis. There was a wide range of differential diagnosis. A battery of tests was requested including autoimmune markers, virology, and imaging. The conclusion that azathioprine was contributing to intrahepatic cholestasis with pregnancy was reached after exclusion of all other differentials. Complications of pregnancy after a kidney transplant include hypertension, pre-eclampsia, deterioration of graft function up to rejection, but also unusual side effects of immunosuppression medication. A twin pregnancy after a second kidney transplant is rare.In addition to bone marrow suppression and elevation of liver enzymes, azathioprine can contribute to intrahepatic cholestasis of pregnancy.Complications of pregnancy after kidney transplant include hypertension, pre-eclampsia, deterioration of graft function up to rejection, but also unusual side effects of immunosuppression medication.

Enhancing photodynamic immunotherapy by reprograming the immunosuppressive tumor microenvironment with hypoxia relief

Tumor hypoxia impairs the generation of reactive oxygen species and the induction of immunogenic cell death (ICD) for photodynamic therapy (PDT), thus impeding its efficacy and the subsequent immunotherapy. In addition, hypoxia plays a critical role in forming immunosuppressive tumor microenvironments (TME) by regulating the infiltration of immunosuppressive tumor-associated macrophages (TAMs) and the expression of programmed death ligand 1 (PD-L1). To simultaneously tackle these issues, a MnO2-containing albumin nanoplatform co-delivering IR780, NLG919, and a paclitaxel (PTX) dimer is designed to boost photodynamic immunotherapy. The MnO2-catalyzed oxygen supply bolsters the efficacy of PDT and PTX-mediated chemotherapy, collectively amplifying the induction of ICD and the expansion of tumor-specific cytotoxic T lymphocytes (CTLs). More importantly, hypoxia releif reshapes the immunosuppressive TME via down-regulating the intratumoral infiltration of M2-type TAMs and the PD-L1 expression of tumor cells to enhance the infiltration and efficacy of CTLs in combination with immune checkpoint blockade (ICB) by NLG919, consequently eradicating primary tumors and almost completely preventing tumor relapse and metastasis. This study sets an example of enhanced immunotherapy for breast cancers through dual ICD induction and simultaneous immunosuppression modulation via both hypoxia relief and ICB, providing a strategy for the treatment of other hypoxic and immunosuppressive cancers.

Acute pancreatitis as a complication of acute COVID-19 in kidney transplant recipients.

Acute pancreatitis is a rare extrapulmonary manifestation of coronavirus disease 2019 (COVID-19) but its full correlation with COVID-19 infection remains unknown. To identify acute pancreatitis' occurrence, clinical presentation and outcomes in a cohort of kidney transplant recipients with acute COVID-19. A retrospective observational single-centre cohort study from a transplant centre in Croatia for all adult renal transplant recipients with a functioning kidney allograft between March 2020 and August 2022 to record cases of acute pancreatitis during acute COVID-19. Data were obtained from hospital electronic medical records. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was proven by a positive SARS-CoV-2 real-time reverse transcriptase-polymerase chain reaction on the nasopharyngeal swab. Four hundred and eight out of 1432 (28.49%) patients who received a renal allograft developed COVID-19 disease. The analyzed cohort included 321 patients (57% males). One hundred and fifty patients (46.7%) received at least one dose of the anti-SARS-CoV-2 vaccine before the infection. One hundred twenty-five (39.1%) patients required hospitalization, 141 (44.1%) developed pneumonia and four patients (1.3%) required mechanical ventilation. Treatment included immunosuppression modification in 233 patients (77.1%) and remdesivir in 53 patients (16.6%), besides the other supportive measures. In the study cohort, only one transplant recipient (0.3%) developed acute pancreatitis during acute COVID-19, presenting with abdominal pain and significantly elevated pancreatic enzymes. She survived without complications with a stable kidney allograft function. Although rare, acute pancreatitis may complicate the course of acute COVID-19 in kidney transplant recipients. The mechanism of injury to the pancreas and its correlation with the severity of the COVID-19 infection in kidney transplant recipients warrants further research.

Enantiomer-Dependent Supramolecular Immunosuppressive Modulation for Tissue Reconstruction.

Modulating the properties of biomaterials in terms of the host immune response is critical for tissue repair and regeneration. However, it is unclear how the preference for the cellular microenvironment manipulates the chiral immune responses under physiological or pathological conditions. Here, we reported that in vivo and in vitro oligopeptide immunosuppressive modulation was achieved by manipulation of macrophage polarization using chiral tetrapeptide (Ac-FFFK-OH, marked as FFFK) supramolecular polymers. The results suggested that chiral FFFK nanofibers can serve as a defense mechanism in the restoration of tissue homeostasis by upregulating macrophage M2 polarization via the Src-STAT6 axis. More importantly, transiently acting STAT6, insufficient to induce a sustained polarization program, then passes the baton to EGR2, thereby continuously maintaining the M2 polarization program. It is worth noting that the L-chirality exhibits a more potent effect in inducing macrophage M2 polarization than does the D-chirality, leading to enhanced tissue reconstruction. These findings elucidate the crucial molecular signals that mediate chirality-dependent supramolecular immunosuppression in damaged tissues while also providing an effective chiral supramolecular strategy for regulating macrophage M2 polarization and promoting tissue injury repair based on the self-assembling chiral peptide design.

Stemness, invasion, and immunosuppression modulation in recurrent glioblastoma using nanotherapy.

The recurrent nature of glioblastoma negatively impacts conventional treatment strategies leading to a growing need for nanomedicine. Nanotherapeutics, an approach designed to deliver drugs to specific sites, is experiencing rapid growth and gaining immense popularity. Having potential in reaching the hard-to-reach disease sites, this field has the potential to show high efficacy in combatting glioblastoma progression. The presence of glioblastoma stem cells (GSCs) is a major factor behind the poor prognosis of glioblastoma multiforme (GBM). Stemness potential, heterogeneity, and self-renewal capacity, are some of the properties that make GSCs invade across the distant regions of the brain. Despite advances in medical technology and MRI-guided maximal surgical resection, not all GSCs residing in the brain can be removed, leading to recurrent disease. The aggressiveness of GBM is often correlated with immune suppression, where the T-cells are unable to infiltrate the cancer initiating GSCs. Standard of care therapies, including surgery and chemotherapy in combination with radiation therapy, have failed to tackle all the challenges of the GSCs, making it increasingly important for researchers to develop strategies to tackle their growth and proliferation and reduce the recurrence of GBM. Here, we will focus on the advancements in the field of nanomedicine that has the potential to show positive impact in managing glioblastoma tumor microenvironment. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

P1091 Cross-domain dynamics of the fungal-bacterial microbiome in patients with ulcerative colitis

Abstract Background Background: Candida in the gut has been recently linked to inflammatory activity in UC. However, the relationship between Candida abundance and the bacterial microbiome remains poorly understood, and how these relationships evolve over disease course in UC is unknown. Methods Methods: We utilized data from the Study of a Prospective Adult Research Cohort with IBD (SPARC-IBD) from IBD Plexus to examine the taxonomic composition of the fungal mycobiome and bacterial microbiome cross-sectionally and longitudinally in time. Differential abundance was assessed using a log-transformed linear model on microbial relative abundances, with a false discovery rate of <0.25. Spearman’s correlations and co-abundance networks were utilized to examine relationships between fungi, bacteria, and disease activity. Changes in fungi and bacteria within-subjects was assessed over 2 timepoints, with respect to clinical inflammatory status, and abundances were compared using Wilcoxon signed rank tests. Results Results: Among 212 patients with UC, 166 patients were in clinical remission (78.3%) while 46 demonstrated clinical activity (21.7%). During clinical activity, there were increases in Candida (q-val<0.05), bacterial family Desulfovibrionaceae (q-val<0.05), and genus Bilophilia (q-val<0.05) [Fig 1A]. During remission, there were reductions in Candida, with increases in family Lachnospiraceae (q-val<0.05), including genus Anaerostipes (q-val=0.09), Blautia (q-val=0.09) and Roseburia (q-val=0.21) [Fig 1B]. Active disease positively correlated with Candida and Desulfovibrionaceae, and negatively correlated with family Lachnospiraceae. During remission, a positive network was present between family Lachnospiraceae, Bifidobacteriaceae, and Eggerthellaceae, which was disrupted during activity, while an antagonistic relationship was evident between Candida and Saccharomyces during remission. Among 25 patients with persistent remission over time (median time interval ~ 4 months), there were no changes in fungal abundances over timepoints. Among patients evolving from activity to remission (n=7), Saccharomyces significantly increased (p-val<0.05), with no significant change in Candida, although there was a trend towards reduction (mean relative abundance at t1=0.28 vs t2=0.11). Concurrently among bacteria, both Bifidobacterium and Anaerostipes significantly increased (p-val<0.05). Conclusions Candida and bacteria from families Lachnospiraceae may have opposing associations with inflammatory status in ulcerative colitis, suggesting they may demonstrate competitive ecological niches. Whether reduction of Candida species may expand protective bacteria should be tested adjunctive to immunosuppressive or microbial modulation therapies.

International consensus on post-transplantation diabetes mellitus.

Post-transplantation diabetes mellitus (PTDM) remains a leading complication after solid organ transplantation. Previous international PTDM consensus meetings in 2003 and 2013 provided standardized frameworks to reduce heterogeneity in diagnosis, risk stratification and management. However, the last decade has seen significant advancements in our PTDM knowledge complemented by rapidly changing treatment algorithms for management of diabetes in the general population. In view of these developments, and to ensure reduced variation in clinical practice, a 3rd international PTDM Consensus Meeting was planned and held from 6-8 May 2022 in Vienna, Austria involving global delegates with PTDM expertise to update the previous reports. This update includes opinion statements concerning optimal diagnostic tools, recognition of prediabetes (impaired fasting glucose and/or impaired glucose tolerance), new mechanistic insights, immunosuppression modification, evidence-based strategies to prevent PTDM, treatment hierarchy for incorporating novel glucose-lowering agents and suggestions for the future direction of PTDM research to address unmet needs. Due to the paucity of good quality evidence, consensus meeting participants agreed that making GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) recommendations would be flawed. Although kidney-allograft centric, we suggest that these opinion statements can be appraised by the transplantation community for implementation across different solid organ transplant cohorts. Acknowledging the paucity of published literature, this report reflects consensus expert opinion. Attaining evidence is desirable to ensure establishment of optimized care for any solid organ transplant recipient at risk of, or who develops, PTDM as we strive to improve long-term outcomes.

Modulation of immunosuppression for long-term graft survival in lamellar pig-to-monkey corneal xenotransplantation from the genetically engineered pig model

Modulation of immunosuppression for long-term graft survival in lamellar pig-to-monkey corneal xenotransplantation from the genetically engineered pig model

Immunogenic Radiation Therapy for Enhanced Antitumor Immunity via a Core-Shell Nanosensitizer-Mediated Immunosuppressive Tumor Microenvironment Modulation.

Due to the immunosuppressive tumor microenvironment (TME) and weak radiation absorption, the immune response triggered by radiation therapy (RT) is limited. Herein, a core-shell nanosensitizer UiO@MnS (denoted as UM) was genuinely constructed for the amplification of RT efficacy and induction of immunogenicity via integrating MnS-reprogrammed TME with Hf-based UiO-sensitized RT. The acid-sensitive MnS would produce H2S under acidic TME to improve oxygenation through inhibition mitochondrial respiration and reducing metabolic oxygen consumption, leading to decreased HIF-1α expression and enhanced radiosensitization. In addition, the generated H2S inhibited the catalase activity to increase the H2O2 level, which subsequently enhanced the Mn2+-mediated Fenton-like reaction, resulting in G2/M cell cycle arrest to improve the cellular sensitivity for radiation. This impressive tumor oxygenation, cell cycle arrest, and radiosensitization procedure boosted RT efficacy and resulted in strong antitumor immunogenicity. Taken together, combining the immunosuppressive TME modulation with a sensitizing radiation strategy shows great promise for magnifying immunogenic RT outputs.

Management of the kidney transplant recipient in the intensive care units.

Kidney transplantation is the ideal treatment for patients with chronic kidney disease and end stage renal disease. While centers are performing more transplants every year, the need for organ transplantation outpaces the supply of organ donors Due to a growing population of patients with advanced kidney disease and a scarcity of kidneys from deceased donors, patients face extended wait times. By the time patients approach transplantation they have multiple comorbidities, in particular cardiovascular complications. Their risk of complications is further compounded by exposure to immunosuppression post kidney transplantation. Kidney transplant recipients (KTRs) are medically complex and may require acute management in the intensive care unit (ICU), as a result of cardiovascular complications, infections, and/or respiratory compromise from lung infections and/or acute pulmonary edema. Acute complication of immunosuppression, such as thrombotic microangiopathy and posterior reversible encephalopathy syndrome may also warrant ICU admission. This review will cover assessment of high-risk complications and management strategies following kidney transplantation. For intensivists caring for KTRs, it is imperative to understand anatomical considerations of the transplanted kidney, unique infectious risks faced by this population, and appropriate modulation of immunosuppression. Recognizing potential complications and implementing appropriate management strategies for KTRs admitted to the ICU will improve kidney allograft and patient survival outcomes.

Preventing Rejection of the Kidney Transplant.

With increasing knowledge of immunologic factors and with the advent of potent immunosuppressive agents, the last several decades have seen significantly improved kidney allograft survival. However, despite overall improved short to medium-term allograft survival, long-term allograft outcomes remain unsatisfactory. A large body of literature implicates acute and chronic rejection as independent risk factors for graft loss. In this article, we review measures taken at various stages in the kidney transplant process to minimize the risk of rejection. In the pre-transplant phase, it is imperative to minimize the risk of sensitization, aim for better HLA matching including eplet matching and use desensitization in carefully selected high-risk patients. The peri-transplant phase involves strategies to minimize cold ischemia times, individualize induction immunosuppression and make all efforts for better HLA matching. In the post-transplant phase, the focus should move towards individualizing maintenance immunosuppression and using innovative strategies to increase compliance. Acute rejection episodes are risk factors for significant graft injury and development of chronic rejection thus one should strive for early detection and aggressive treatment. Monitoring for DSA development, especially in high-risk populations, should be made part of transplant follow-up protocols. A host of new biomarkers are now commercially available, and these should be used for early detection of rejection, immunosuppression modulation, prevention of unnecessary biopsies and monitoring response to rejection treatment. There is a strong push needed for the development of new drugs, especially for the management of chronic or resistant rejections, to prolong graft survival. Prevention of rejection is key for the longevity of kidney allografts. This requires a multipronged approach and significant effort on the part of the recipients and transplant centers.

A quick algorithmic review on management of viral infectious diseases in pediatric solid organ transplant recipients.

Pediatric solid organ transplant is a life-saving procedure for children with end-stage organ failure. Viral infections are a common complication following pediatric solid organ transplantation (SOT), which can lead to increased morbidity and mortality. Pediatric solid organ transplant recipients are at an increased risk of viral infections due to their immunosuppressed state. The most commonly encountered viruses include cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), varicella-zoster virus (VZV), adenoviruses, and BK polyomavirus. Prevention strategies include vaccination prior to transplantation, post-transplant prophylaxis with antiviral agents, and preemptive therapy. Treatment options vary depending on the virus and may include antiviral therapy and sometimes immunosuppression modification. This review provides a Quick Algorithmic overview of prevention and treatment strategies for viral infectious diseases in pediatric solid organ transplant recipient.

Tumour-associated macrophages in gastric cancer: From function and mechanism to application.

Gastric cancer (GC) is a malignant tumour, with high morbidity and mortality rates worldwide. The occurrence and development of GC is a complex process involving genetic changes in tumour cells and the influence of the surrounding tumour microenvironment (TME). Accumulative evidence shows that tumour-associated macrophages (TAMs) play a vital role in GC, acting as plentiful and active infiltrating inflammatory cells in the TME. In this review, the different functions and mechanisms of TAMs in GC progression, including the conversion of phenotypic subtypes; promotion of tumour proliferation, invasion and migration; induction of chemoresistance; promotion of angiogenesis; modulation of immunosuppression; reprogramming of metabolism; and interaction with the microbial community are summarised. Although the role of TAMs in GC remains controversial in clinical settings, clarifying their significance in the treatment selection and prognostic prediction of GC could support optimising TAM-centred clinicaltherapy. In summary, we reviewed the the phenotypic polarisation, function and molecular mechanism of TAMs and their potential applications in the treatment selection and prognostic prediction of GC.

BI05 How do we manage organ transplant recipients after their first cutaneous squamous cell carcinoma: the UK multicentre Contemporary Outcomes After cutaneous SCC in Transplant recipients study

Abstract Cutaneous squamous cell carcinoma (cSCC) is the most common malignancy in organ transplant recipients (OTRs). Previous studies have shown that up to 75% of OTRs develop further skin cancer after their first cSCC. Interventions aimed at reducing this risk include modification of immunosuppression. However, a recent Delphi study has highlighted the lack of evidence regarding the optimal timing and nature of immunosuppression modification, and the frequency of utilization and impact of this approach at time of first cSCC is unknown. The COAST (Contemporary Outcomes After cutaneous SCC in Transplant recipients) study is a multicentre retrospective cohort study aiming to investigate contemporary management and outcomes after the first cSCC in kidney transplant recipients in the UK as a baseline for informing future interventional studies. We identified 119 consecutive kidney/kidney–pancreas transplant recipients across six centres in whom a first-ever cSCC was histologically confirmed. Median cumulative duration of immunosuppression to first cSCC was 143 months (range 5–480), median age at diagnosis was 63 years (range 44–87), 77% were male, 24% had a previous transplant, 37% had a previous skin malignancy other than cSCC and 8% had two or more cSCCs excised at the same time. Two-thirds of the first cSCCs were located on the head and neck, the median diameter was 12 mm (range 2–60) and TNM staging was T1 (64%), T2 (17%) and T3 (20%). After the first cSCC, 20% of OTRs had another cSCC within 12 months, 30% by 24 months and > 50% by 4 years. During the immediate follow-up (within 6 months of the first cSCC), immunosuppression was modified in 32.8% (n = 39/119) of patients (immunosuppression arm), and in 41% (n = 16/39) it was explicitly stated to be a result of cSCC diagnosis. During a median follow-up of 36 months (range 0–80; interquartile range 24–52), 21/39 (54%) in the IM arm had further cSCC(s), seven (17.9%) had metastatic cSCC, nine (23%) had graft loss, five (13%) developed further noncutaneous malignancies and 11 (28%) died during follow-up. In the nonimmunosuppression arm (n = 79), 31 (39%) had further cSCC(s), 6 (8%) had metastatic cSCC, 13 (16%) had graft loss, eight (10%) developed further noncutaneous malignancies and 18 (23%) died during follow-up. In this study, early modification of immunosuppression following a cSCC diagnosis was not associated with improved cancer-related outcomes. This may partly be explained by confounders, possible clinician selection of high-risk patients for immunosuppression modification, the 6-month window studied and the small sample size, which is the subject of ongoing analyses. Further prospective studies are urgently needed to evaluate the optimal timing and regime for immunosuppression modification for optimizing patient outcomes.

Immune Checkpoint Inhibitors in Solid Organ Transplant Recipients With Advanced Skin Cancers-Emerging Strategies for Clinical Management.

Use of immune checkpoint inhibitors (ICIs) in solid organ transplant recipients (SOTRs) with advanced skin cancers presents a significant clinical management dilemma. SOTRs and other immunosuppressed patients have been routinely excluded from ICI clinical trials with good reason: immune checkpoints play an important role in self- and allograft-tolerance and risk of acute allograft rejection reported in retrospective studies affects 10% to 65% of cases. These reports also confirm that cutaneous squamous cell carcinoma and melanoma respond to ICI therapy, although response rates are generally lower than those observed in immunocompetent populations. Prospective trials are now of critical importance in further establishing ICI efficacy and safety. However, based on current knowledge, we recommend that ICIs should be offered to kidney transplant recipients with advanced cutaneous squamous cell carcinoma, melanoma, or Merkel cell carcinoma if surgery and/or radiotherapy have failed. For kidney transplant recipients, this should be first line ahead of chemotherapy and targeted therapies. In SOTRs, the use of ICIs should be carefully considered with the benefits of ICIs versus risks of allograft rejection weighed up on a case-by-case basis as part of shared decision-making with patients. In all cases, parallel management of immunosuppression may be key to ICI responsiveness. We recommend maintaining immunosuppression before ICI initiation with a dual immunosuppressive regimen combining mammalian target of rapamycin inhibitors and either corticosteroids or calcineurin inhibitors. Such modification of immunosuppression must be considered in the context of allograft risk (both rejection and also its subsequent treatment) and risk of tumor progression. Ultimately, a multidisciplinary approach should underpin all clinical decision-making in this challenging scenario.

Transforming growth factor-b1 and soluble co-inhibitory immune checkpoints as putative drivers of immune suppression in advanced basal cell carcinoma.

9567 Background: BCC rarely metastasizes and the mortality rate is low; however, the disease is associated with substantial morbidity. Transforming growth factor-b1 (TGF-b1) is a key player in cell proliferation, differentiation, apoptosis, and immune regulation. TGF-b1 is associated with immunosuppression and resistance to immunotherapeutic drugs. Immune checkpoint proteins (ICMs) maintain self-tolerance and modulate the immune responses of effector cells. The current study compared the levels and possible associations between systemic soluble ICMs (sICMs) and a group of humoral modulators of immune suppressor cells in a cohort of patients with advanced basal cell carcinoma (BCC, n = 40) and a group of healthy control subjects (n = 20). Methods: We measured sICMs and immunosuppressive humoral modulators by using multiplex bead array or ELISA procedures, with plasma as the matrix. The sICMs comprised seven co-inhibitory (CTLA-4, BTLA, LAG-3, PD-1, PDL-1, PDL-2, and TIM-3) and eight co-stimulatory (CD27, CD28, CD40, CD80, CD86, GITR, GITRL, and ICOS) proteins, as well as the two dual-active sICPs, HVEM and TLR2. The seven humoral modulators of immunosuppressor cells included arginase 1, fibroblast activation protein (FAP), RANTES (Regulated upon Activation Normal T Cell Expressed and Presumably Secreted) also known as CCL5, interleukin-10 (IL-10), TGF-b1, and the M2-type macrophage biomarkers, soluble CD163 (sCD163) and sCD206. Ethics approval was granted by The Research Ethics Committee, Faculty of Health Sciences, University of Pretoria (Ethics Committee Approval Numbers 356/2020. Results: The plasma levels of six co-inhibitory sICPs, sCTLA-4, sLAG-3, sPD-1, sPD-L1, and sTIM-3 and sPD-L2 were significantly elevated in the cohort of BCC patients ( p< 0.001- p< 0.00001), while that of sBTLA was significantly decreased ( p< 0.006). Of the co-stimulatory sICPs, sCD27 was significantly increased ( p <0.0002) in the cohort of BCC patients, with the levels of the others essentially comparable with those of the control patients; of the dual active sICPs, sHVEM, sTLR2 was significantly elevated ( p< 0.00001) and TLR2 comparable with the control group. Although the plasma levels of the seven modulators of immune suppressor function were not significantly different between the BCC and control groups, correlation heat maps revealed selective, strong associations of TGF-b1 with seven co-stimulatory (z = 0.618468-0.768131) and 4 co-inhibitory (z = 0.674040-0.808365) sICPs, as well as with sTLR2 (z = 0.696431). Conclusions: Notwithstanding the association of BCC with selective elevations in the levels of a large group of co-inhibitory sICPs, our novel findings also imply the probable involvement of TGF-b1 in driving immunosuppression in this malignancy, possibly via activation of regulatory T cells.