Umbilical Cord Blood Transplantation for Fanconi Anemia With a Special Focus on Late Complications: a Study on Behalf of Eurocord and SAAWP-EBMT.

Hematopoietic cell transplantation (HCT) remains the sole available curative treatment for Fanconi anemia (FA), with particularly favorable outcomes reported after matched sibling donor (MSD) HCT. This study aimed to describe outcomes, with a special focus on late complications, of FA patients who underwent umbilical cord blood transplantation (UCBT). In this retrospective analysis of allogeneic UCBT for FA performed between 1988 and 2021 in European Society for Blood and Marrow Transplantation (EBMT)-affiliated centers, a total of 205 FA patients underwent UCBT (55 related and 150 unrelated) across 77 transplant centers. Indications for UCBT were bone marrow failure in 190 patients and acute leukemia/myelodysplasia in 15 patients. The median age at transplantation was 9 years (range, 1.2 to 43 years), with only 20 patients aged >18 years. Among the donor-recipient pairs, 56% (n = 116) had a 0 to 1/6 HLA mismatch. Limited-field radiotherapy was administered to 28% (n = 58) and 78% (n = 160) received a fludarabine (Flu)-based conditioning regimen. Serotherapy consisted of antithymocyte globulin (n = 159; 78%) or alemtuzumab (n = 12; 6%). The median follow-up was 10 years for related UCBT and 7 years for unrelated UCBT. Excellent outcomes were observed in the setting of related UCBT, including a 60-day cumulative incidence (CuI) of neutrophil recovery of 98.1% (95% confidence interval [CI], 93.9% to 100%), a 100-day CuI of grade II-IV acute graft-versus-host disease (GVHD) of 17.3% (95% CI, 9.5% to 31.6%), and a 5-year CuI of chronic GVHD (cGVHD) of 22.7% (95% CI, 13.3% to 38.7%; 13% extensive). Five-year overall survival (OS) was 88%. In multivariate analysis, none of the factors included in the model predicted a better OS. In unrelated UCBT, the 60-day CuI of neutrophil recovery was 78.7% (95% CI, 71.9% to 86.3%), the 100-day CuI of grade II-IV aGVHD was 31.4% (95% CI, 24.6% to 40.2%), and the 5-year CuI of cGVHD was 24.3% (95% CI, 17.8% to 32.2%; 12% extensive). Five-year OS was 44%. In multivariate analysis, negative recipient cytomegalovirus serology, Flu-based conditioning, age <9 years at UCBT, and 0 to 1/6 HLA mismatch were associated with improved OS. A total of 106 patients, including 5 with acute leukemia/myelodysplasia, survived for >2 years after UCBT. Nine of these patients developed subsequent neoplasms (SNs), including 1 donor-derived acute myelogenous leukemia and 8 solid tumors, at a median of 9.7 years (range, 2.3 to 21.8 years) post-UCBT (1 related and 8 unrelated UCBT). In a subset of 49 patients with available data, late nonmalignant complications affecting various organ systems were observed at a median of 8.7 years (range, 2.7 to 28.8 years) post-UCBT. UCB is a valid source of stem cells for transplantation in patients with FA, with the best results observed after related UCBT. After unrelated UCBT, improved survival was observed in patients who underwent transplantation at a younger age, with Flu-based conditioning, and with better HLA parity. The incidence of organ-specific complications and SNs was relatively low. The incidence of SNs, mostly squamous cell carcinoma, increases with time. Rigorous follow-up and lifelong screening are crucial in survivors of UCBT for FA.

HLA peptide-binding pocket diversity modulates immunological complications after cord blood transplant in acute leukaemia.

Pocket motifs and their amino acid positions of HLA molecules are known to govern antigen presentation to effector cells. Our objective was to analyse their influence on the risk of graft-versus-host disease (GVHD) and relapse after umbilical cord blood transplant (UCBT). The transplant characteristics of 849 patients with acute leukaemia were obtained from the Eurocord/EBMT database. Higher acute (a) GVHD was associated with homozygosity of UCB HLA-C amino acid positions 77 and 80 (NN/KK) (p = 0.008). Severe aGVHD was associated with HLA-A pocket B YSAVMENVHY motif (p = 0.002) and NN and RR genotypes of the HLA-C amino acid positions 77 and 156 (p = 0.006 and p = 0.002). Such risk was also increased in case of recipient and UCB mismatches in P4 (p < 0.0001) and P9 (p = 0.003) pockets of HLA-DQB1 alleles. For chronic GVHD, the pocket B YYAVMEISNY motif of the HLA-B*15:01 allele and the absence of mismatch between recipient and UCB in the P6 pocket of HLA-DRB1 were associated with a lower risk (p = 0.0007 and p = 0.0004). In relapse, both UCB pocket B YFAVMENVHY belonging to HLA-A*32:01 and recipient pocket B YDSVGENYQY motif of the HLA-C*07:01 allele were associated with higher risk (p = 0.0026 and p = 0.015). We provide clues on HLA-mediated cellular interactions and their role in the development of GVHD and relapse.

Cord blood transplantation for adult mature lymphoid neoplasms in Europe and Japan.

ABSTRACT: To clarify the different characteristics and prognostic factors of cord blood transplantation (CBT) in adult patients with lymphoid neoplasms in Europe and Japan, we conducted a collaborative study. Patients aged 18-75 years receiving their first CBT (Europe: single CBT, n = 192; double CBT, n = 304; Japan: single CBT, n = 1150) in 2000-2017 were analyzed. Fewer patients with Hodgkin lymphoma (Europe vs Japan, 26% vs 5%), and older patients (≥50 years) (39% vs 59%) with a higher refined disease risk index (rDRI) (high-very high: 49% vs 14%) were included in the Japanese registry. High-very high rDRI was associated with inferior overall survival (OS) (vs low rDRI, Europe: hazard ratio [HR], 1.87; P = .001; Japan: HR, 2.34; P < .001) with higher progression/relapse risks. Total body irradiation (TBI)-containing conditioning contributed to superior OS both in Europe (vs TBI-reduced-intensity conditioning [RIC], non-TBI-RIC: HR, 1.93; P < .001; non-TBI-Myeloablative conditioning [MAC]: HR, 1.90; P = .003) and Japan (non-TBI-RIC: HR, 1.71; P < .001; non-TBI-MAC: HR 1.50, P = .007). The impact of HLA mismatches (≥2) on OS differed (Europe: HR, 1.52; P = .007; Japan: HR, 1.18; P = .107). CBT for lymphoid neoplasms, especially in those with high rDRI showed poor outcomes despite all the different characteristics in both registries. TBI should be considered in conditioning regimens to improve these outcomes. The different impacts of HLA mismatches call attention to the fundamental differences among these populations.

Impact of allele-level HLA matching on outcomes after double cord blood transplantation in adults with malignancies.

In single unrelated cord blood transplantation (UCBT), an increasing number of HLA allele mismatches (MM) has been associated with inferior overall survival (OS) and attributed to higher transplant-related mortality (TRM). Previous studies on the role of allele-level HLA matching after double UCBT (dUCBT) showed conflicting results. In this study, we report the impact of allele-level HLA matching on the outcomes of a large dUCBT cohort. We included 963 adults with hematologic malignancies, with available allele-level HLA matching at HLA-A, -B, -C, and -DRB1, receiving dUCBT between 2006 to 2019. Assignment of donor-recipient HLA match was performed considering the unit with the highest disparity with the recipient. Three hundred ninety-two patients received dUCBT with 0 to 3 MM and 571 with ≥4 allele MM. For recipients of dUCBT with 0 to 3 MM, day-100 and 4-year TRM were 10% and 23%, respectively, compared with 16% and 36% for those with ≥4 MM. A higher degree of allele MM was also associated with the worse neutrophil recovery and lower incidence of relapse; no significant effect on graft-versus-host disease was observed. Patients receiving units with 0 to 3 MM had a 4-year OS of 54% compared with 43% for those receiving units with ≥4 MM. The inferior OS associated with higher HLA disparity was only partially mitigated by increased total nucleated cell doses. Our results confirm that allele-level HLA typing is a significant factor for OS after dUCBT, and units with ≥4 MM (≤4/8 HLA-matched) should be avoided if possible.

Comparative analysis of the variability of the human leukocyte antigen peptide-binding pockets in patients with acute leukaemia.

The association between acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) and the human leukocyte antigens (HLA) has rarely been studied in terms of diversity of peptide-binding pockets. The objective of this study was to analyse whether motifs of HLA class I and class II peptide-binding pockets and/or their amino acid positions were differentially associated with ALL and AML. We included 849 patients from the Eurocord/European Blood and Marrow Transplant registry. The HLA peptide-binding pockets whose amino acid variability was analysed were B and F for HLA class I, P4, P6, and P9 for HLA-DRB1, and P4 and P9 for HLA-DQB1. The motif RFDRAY in P4 of HLA-DRB1*16:01/02/03/05 alleles and the motif YYVSY in P9 of HLA-DQB1*05:02/04/05 alleles, were statistically associated with ALL (corrected p value [pc ] = 0.001 and pc  = 0.035 respectively). The frequency of serine 57 in the P9 of HLA-DQB1 was higher in ALL (odds ratio 2.09, 95% confidence interval: 1.27-3.44; pc  = 0.037). Our analysis suggests that specific motifs in terms of HLA class II pockets and amino acids might be unique to ALL. The associations identified in this study encourage further investigation oF the role of HLA peptide-binding pockets and their amino acids in immune processes underpinning acute leukaemia and ultimately in immunotherapy settings.

Outcomes of subsequent neoplasms after umbilical cord blood transplantation in Europe.

Subsequent neoplasms (SNs) compromise long-term survivors after hematopoietic cell transplantation. We performed a retrospective analysis of SNs in 10 358 recipients of umbilical cord blood transplantation (UCBT) from 1988 to 2018. SNs developed in 233 patients and 84 were of pediatric age. Indications for UCBT were malignant hematological diseases in 199 patients (85%). Three groups of SNs were observed. Posttransplant lymphoproliferative disorders (PTLD) were reported in 145 patients in a median of 4 months after UCBT. Of these, 9 patients died from relapse, 83 from PTLD, and 24 from transplant-related causes. At last follow-up, 29 were alive; 5-year overall survival (OS) after PTLD diagnosis was 21%. Acute leukemia/myelodysplasia (AL/MDS) was diagnosed in 23 patients in a median of 28 months after UCBT and included 3 donor-cell AL. Four of 23 patients died from relapse of primary disease, 8 from progression of SNs, and 4 from TRM. Seven patients remain alive; the 5-year OS after AL/MDS diagnosis was 36%. Solid tumors (ST) were reported in 65 patients in a median of 54 months after UCBT. Most common tumor sites were lung, thyroid, bone, and soft tissue. A total of 33 patients died (26 owing to ST, 6 to relapse of primary disease, and 1 cause missing). At last follow-up, 32 of 65 patients were alive; the 5-year OS after the diagnosis of ST was 51%. In conclusion, despite their poor outcomes, SNs that occur after UCBT are extremely rare. Identification of risk factors and early detection may help to improve OS.

Possible Effect of the use of Mesenchymal Stromal Cells in the Treatment of Autism Spectrum Disorders: A Review.

Autism spectrum disorder (ASD) represents a set of heterogeneous neurodevelopmental conditions defined by impaired social interactions and repetitive behaviors. The number of reported cases has increased over the past decades, and ASD is now a major public health burden. So far, only treatments to alleviate symptoms are available, with still unmet need for an effective disease treatment to reduce ASD core symptoms. Genetic predisposition alone can only explain a small fraction of the ASD cases. It has been reported that environmental factors interacting with specific inter-individual genetic background may induce immune dysfunctions and contribute to the incidence of ASD. Such dysfunctions can be observed at the central level, with increased microglial cells and activation in ASD brains or in the peripheral blood, as reflected by high circulating levels of pro-inflammatory cytokines, abnormal activation of T-cell subsets, presence of auto-antibodies and of dysregulated microbiota profiles. Altogether, the dysfunction of immune processes may result from immunogenetically-determined inefficient immune responses against a given challenge followed by chronic inflammation and autoimmunity. In this context, immunomodulatory therapies might offer a valid therapeutic option. Mesenchymal stromal cells (MSC) immunoregulatory and immunosuppressive properties constitute a strong rationale for their use to improve ASD clinical symptoms. In vitro studies and pre-clinical models have shown that MSC can induce synapse formation and enhance synaptic function with consequent improvement of ASD-like symptoms in mice. In addition, two preliminary human trials based on the infusion of cord blood-derived MSC showed the safety and tolerability of the procedure in children with ASD and reported promising clinical improvement of core symptoms. We review herein the immune dysfunctions associated with ASD provided, the rationale for using MSC to treat patients with ASD and summarize the current available studies addressing this subject.

Umbilical Cord Blood Transplantation after Graft Failure from a Previous Hematopoietic Stem Cell Transplantation.

Graft failure (GF) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HCT). In the absence of autologous recovery, a second HCT is necessary to attempt to prevent death due to prolonged pancytopenia. Previous studies describing outcomes of second HCT performed after GF with different types of donor sources report wide ranges of overall survival (OS) and transplantation-related mortality (TRM); however, studies including a large number of patients undergoing a second HCT with umbilical cord blood (UCB) as the graft source are scarce. This retrospective registry-based study examined data extracted from Eurocord and the European Society for Blood and Marrow Transplantation (EBMT) databases to evaluate outcomes of 247 UCBTs performed in EBMT transplant centers after GF following a previous HCT. Data were analyzed separately for patients with malignant diseases (n = 141) and those with nonmalignant diseases (n = 106). The most frequent HCT that resulted in GF was also UCBT (65.0% for patients with malignant diseases and 68.9% for those with nonmalignant diseases), and most GFs occurred within 100 days after transplantation (92.3% and 85.9%, respectively). The median follow-up was 47 months for surviving patients with malignant diseases and 38 months for those with nonmalignant diseases. We observed a similar cumulative incidence of neutrophil engraftment of 59.1% (95% confidence interval [CI], 51.4% to 67.9%) and 60.4% (95% CI, 51.7%-70.6%), respectively, at a median time of 23 days and 24 days, correspondingly. The 3-year OS was 28.9% (95% CI, 21.8% to 37.3%) in the malignant disease group and 49.1% (95% CI, 39.5%-58.8%) in the nonmalignant disease group. In patients with malignancies, TRM was 39.9% (95% CI, 32.5% to 49.1%) at 100 days and 57.5% (95% CI, 49.4%-66.8%) at 3 years. In multivariate analyses, none of the characteristics studied was statistically significantly associated with engraftment or OS. Although survival is not optimal in patients requiring a second HCT, UCBT remains a valid life-saving option for patients with GF.

Systematic Review/Meta-Analysis on Efficacy of Allogeneic Hematopoietic Cell Transplantation in Sickle Cell Disease: An International Effort on Behalf of the Pediatric Diseases Working Party of European Society for Blood and Marrow Transplantation and the Sickle Cell Transplantation International Consortium.

Sickle cell disease (SCD) affects more than 300,000 children annually worldwide. Despite improved supportive care, long-term prognosis remains poor. Allogeneic hematopoietic cell transplantation (allo-HCT) is the sole validated curative option, resulting in sustained resolution of the clinical phenotype. The medical literature on allo-HCT for SCD is largely limited to children. Recent studies have evaluated allo-HCT efficacy in adults. Here, we conducted a systematic review/meta-analysis to assess the totality of evidence on the efficacy, or lack thereof, of allo-HCT in treating SCD. We performed a comprehensive literature search using PubMed/Medline, Embase, and Cochrane library databases on November 13, 2019. Four authors independently extracted data on clinical outcomes related to benefits (overall survival [OS] and disease-free survival [DFS]) and harms (acute graft-versus-host disease [aGVHD], chronic graft-versus-host disease [cGVHD], nonrelapse mortality [NRM], and graft failure [GF]). Our search identified a total of 1906 references. Only 33 studies (n= 2853 patients) met our inclusion criteria. We also performed a subset analysis by age. Analyses of all-age groups showed pooled rates of 96% for OS, 90% for DFS, 20% for aGVHD, 10% for cGVHD, 4% for NRM, and 5% for GF. In the pediatric population, pooled rates for OS, DFS, aGVHD, cGVHD, NRM, and GF were 97%, 91%, 26%, 11%, 5%, and 3%, respectively. In adults, pooled rates for OS, DFS, aGVHD, cGVHD, NRM, and GF were 98%, 90%, 7%, 1%, 0%, and 14%, respectively. Our data show that allo-HCT is safe and effective, yielding pooled OS rates exceeding 90%. The high GF rate of 14% in adults is concerning and emphasizes the need to evaluate new strategies.

Polymorphisms in Inflammatory Genes Modulate Clinical Complications in Patients With Sickle Cell Disease.

Sickle cell disease (SCD), the most common monogenic disease worldwide, is marked by a phenotypic variability that is, to date, only partially understood. Because inflammation plays a major role in SCD pathophysiology, we hypothesized that single nucleotide polymorphisms (SNP) in genes encoding functionally important inflammatory proteins might modulate the occurrence of SCD complications. We assessed the association between 20 SNPs in genes encoding Toll-like receptors (TLR), NK cell receptors (NKG), histocompatibility leukocyte antigens (HLA), major histocompatibility complex class I polypeptide-related sequence A (MICA) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and the occurrence of six SCD clinical complications (stroke, acute chest syndrome (ACS), leg ulcers, cholelithiasis, osteonecrosis, or retinopathy). This study was performed in a cohort of 500 patients. We found that the TLR2 rs4696480 TA, TLR2 rs3804099 CC, and HLA-G, rs9380142 AA genotypes were more frequent in patients who had fewer complications. Also, in logistic regression, the HLA-G rs9380142 G allele increased the risk of cholelithiasis (AG vs. AA, OR 1.57, 95%CI 1.16-2.15; GG vs. AA, OR 2.47, 95%CI 1.34-4.64; P = 0.02). For SNPs located in the NKG2D loci, in logistic regression, the A allele in three SNPs was associated with a lower frequency of retinopathy, namely, rs2246809 (AA vs. GG: OR 0.22, 95%CI 0.09-0.50; AG vs. GG: OR 0.47, 95%CI 0.31-0.71; P = 0.004, for patients of same origin), rs2617160 (AT vs. TT: OR 0.67, 95%CI 0.48-0.92; AA vs. TT: OR 0.45, 95%CI 0.23-0.84; P = 0.04), and rs2617169 (AA vs. TT: OR 0.33, 95%CI 0.13-0.82; AT vs. TT: OR 0.58, 95%CI 0.36-0.91, P = 0.049, in patients of same SCD genotype). These results, by uncovering susceptibility to, or protection against SCD complications, might contribute to a better understanding of the inflammatory pathways involved in SCD manifestations and to pave the way for the discovery of biomarkers that predict disease severity, which would improve SCD management.

HLA-Matched Unrelated Donors for Patients with Sickle Cell Disease: Results of International Donor Searches.

Sickle cell disease (SCD) is the most common inherited hemoglobinopathy. Hematopoietic stem cell transplantation (HCT) is the sole curative therapy for SCD, but few patients will have a matched sibling donor. Patients with SCD are mostly of African origin and thus are less likely to find a matched unrelated donor in international registries. Using HaploStats, we estimated HLA haplotypes for 185 patients with SCD (116 from a Brazilian center and 69 from European Society for Blood and Marrow Transplantation [EBMT] centers) and classified the ethnic origin of haplotypes. Then we assessed the probability of finding an HLA-matched unrelated adult donor (MUD), considering loci A, B, and DRB1 (6/6), in international registries. Most haplotypes were African, but Brazilians showed a greater ethnic admixture than EBMT patients. Nevertheless, the chance of finding at least one 6/6 potential allelic donor was 47% for both groups. Most potential allelic donors were from the US National Marrow Donor Program registry and from the Brazilian REDOME donor registry. Although the probability of finding a donor is higher than previously reported, strategies are needed to improve ethnic diversity in registries. Moreover, predicting the likelihood of having an MUD might influence SCD management.

Alternative donor hematopoietic stem cell transplantation for sickle cell disease in Europe.

Allogeneic hematopoietic stem cell transplantation (HSCT) is, to date, the only curative treatment for sickle cell disease (SCD). Because an human leukocyte antigen (HLA)-matched sibling donor is not always available, alternative stem cell sources such as unrelated or haploidentical related donors have been explored. To date, few series of SCD patients transplanted with an unrelated donor, cord blood, and haploidentical related donor have been reported, but the high rates of rejection and chronic graft versus host disease have limited their widespread application. We describe the outcomes of a retrospective, registry-based, survey on 144 alternative donor HSCT performed for SCD in 30 European Society for Blood and Marrow Transplantation centers between 1999 and 2017. Data on 70 unrelated adult donors (49%), six cord blood (4%), and 68 haploidentical donors (47%; including post-HSCT Cy, ex vivo T-cell depleted, and other haplo-HSCTs) were reported and missing information was updated by the centers. Overall, 16% patients experienced graft failure, Grade II-IV acute GVHD at 100 days was 24%, whereas Grade III-IV was 10%. Chronic GVHD was observed in 24% (limited for 13 patients and extensive for 18 patients). Overall, the 3-year overall survival (OS) was 86% ± 3% and 3-year event-free survival (EFS; considering death and graft failure as events) was 72% ± 4%. We therefore conclude that alternative donor HSCT for SCD can be feasible but efforts in decreasing relapse and GVHD should be promoted to increase its safe and successful utilization. Moreover, a better knowledge of HLA matching and the tailoring of conditioning could help improve EFS and OS.

Optimization of the Enzymatic Hydrolysis of Lupin (Lupinus) Proteins for Producing ACE-Inhibitory Peptides.

Recently, the enzymatic hydrolysis of Lupinus albus and Lupinus angustifolius proteins with pepsin was showed to produce peptides able to inhibit the angiotensin-converting enzyme (ACE). The objective of the present work was to test different hydrolytic enzymes and to investigate three lupin species (L. albus, L. angustifolius, Lupinus luteus) with the final goal of selecting the best enzyme/species combination for an efficient production of ACE-inhibitory peptide mixtures. Pepsin gave peptides with the best IC50 values (mean value on three species 186 ± 10 µg/mL), followed by pepsin + trypsin (198 ± 16 µg/mL), chymotrypsin (213 ± 83 µg/mL), trypsin (405 ± 54 µg/mL), corolase PP (497 ± 32 µg/mL), umamizyme (865 ± 230 µg/mL), and flavourzyme (922 ± 91 µg/mL). The three species showed similar activity scales, but after pepsin + trypsin and chymotrypsin treatments, L. luteus peptide mixtures resulted to be significantly the most active. This investigation indicates that lupin proteins may be a valuable source of ACE-inhibitory peptides, which may explain the activity observed in experimental and clinical studies and foresee the application of lupin proteins into functional foods or dietary supplements.

ACE-inhibitory activity of enzymatic protein hydrolysates from lupin and other legumes.

The objective of this investigation was to compare the angiotensin converting enzyme (ACE)-inhibitory activity of the hydrolysates obtained by pepsin digestion of proteins of some legumes, such as chickpea, common bean, lentil, lupin, pea, and soybean, by using the same experimental procedure. The ACE-inhibitory activity was measured by using the tripeptide hippuryl-histidyl-leucine (HHL), as model peptide, and HPLC-DAD, as analytical method. The peptide mixtures of all legumes were active, with soybean and lupin the most efficient, with IC50 values of 224 and 226 µg/ml, respectively. Considering the promising results obtained with lupin, and aiming to identify the protein(s) that release(s) the peptides responsible for the activity, the peptides obtained from the pepsin digestion of some industrial lupin protein isolates and purified protein fractions were tested. The most active mixture, showing an IC50 value of 138 µg/ml, was obtained hydrolysing a mixture of lupin α+ß conglutin.

Secretome analysis of multiple pancreatic cancer cell lines reveals perturbations of key functional networks.

The cancer secretome is a rich repository in which to mine useful information for both cancer biology and clinical oncology. To help understand the mechanisms underlying the progression of pancreatic cancer, we characterized the secretomes of four human pancreatic ductal adenocarcinoma (PDAC) cell lines versus a normal counterpart. To this end, we used a proteomic workflow based on high-confidence protein identification by mass spectrometry, semiquantitation by a label-free approach, and network enrichment analysis by a system biology tool. Functional networks significantly enriched with PDAC-dysregulated proteins included not only expected alterations within key mechanisms known to be relevant for tumor progression (e.g., cell-cell/cell-matrix adhesion, extracellular matrix remodeling, and cytoskeleton rearrangement), but also other extensive, coordinated perturbations never observed in pancreatic cancer. In particular, we highlighted perturbations possibly favoring tumor progression through immune escape (i.e., inhibition of the complement system, deficiency of selected proteasome components within the antigen-presentation machinery, and inhibition of T cell cytoxicity), and a defective protein folding machinery. Among the proteins found concordantly oversecreted in all of our PDAC cell lines, many are reportedly overexpressed in pancreatic cancer (e.g., CD9 and Vimentin), while others (PLOD3, SH3L3, PCBP1, and SFRS1) represent novel PDAC-secreted proteins that may be worth investigating.