Abstract In colorectal cancer (CRC), tumours classified as consensus molecular subtype 4 (CMS4) have the worst prognosis and derive negligible benefit from chemotherapy. We previously described how repressed interferon-related signalling is associated with increased relapse in CMS4 tumours. Although the viral mimetic polyinosinic:polycytidylic acid, poly(I:C), can reduce liver metastasis in vivo, the initial phenotypic changes that underpin its anti-metastatic response remain poorly described, particularly in the immunosuppressed CMS4 tumour microenvironment. Here we characterise lineage-specific anti-metastatic responses induced by poly(I:C), including acute macrophage polarisation and a novel CMS1-like regenerative stem cell state, which drive pro-inflammatory microenvironmental changes in CRC. These insights enabled the development of tractable biomarkers that identify an “immune-warm” patient subset most likely to respond to poly(I:C), enriched for mismatch-repair proficient (pMMR), anti-inflammatory macrophages and CMS4-like features. The viral mimetic poly(I:C) offers a tailored treatment option for poor-prognostic tumours, by reprogramming stem cell states and activation of an innate-adaptive anti-metastatic response.

Background The immunosuppressive tumor microenvironment reduces immune response effectiveness in stromal-rich tumors, including consensus molecular subtype 4 colorectal cancer (CRC). Mesenchymal stromal cells (MSCs), precursors to cancer-associated fibroblasts (CAFs), promote cancer progression by suppressing anti-tumor immune responses. Hypersialylation of glycans on tumors engages Siglec receptors on immune cells, driving immune dysfunction, but its role in stromal-mediated suppression of innate immunity remains unclear.Methods Sialylation, Sialic acids and Siglec ligands were measured on CRC tissue, primary human normal-associated fibroblasts (NAFs), CAFs, and tumor-conditioned MSCs (MSCTCS) using transcriptional profiles, immunohistochemistry and flow cytometry, respectively. The effect of stromal cell sialylation on macrophages and NK cells was assessed in ex vivo human primary stromal and immune cell co-cultures, and expression of Siglec-10 and immune cell phenotype markers and function was measured by flow cytometry and real-time imaging. Using an immunocompetent Balb/c CT26 mouse model, we induced tumors with/without conditioned stromal cells, with/without pretreatment of stromal cells with sialyltransferase inhibitor (3FAX) or sialidase (E610). We assessed the effect of stromal cell sialylation on macrophages and NK cells in the tumor and secondary lymphoid tissues by flow cytometry.Results Stromal cells, including CAFs, in CRC tumors are highly sialylated compared with epithelial cancer cells and are associated with high expression of the sialyltransferase ST6GALNAC6. Genetic knockdown of ST6GALNAC6 reduced the expression of stromal cell Siglec-10 ligands in MSCs. CAFs and MSCTCS induced Siglec-10 on macrophages and NK cells and impaired macrophage phagocytosis and NK cell cytotoxicity. Sialidase treatment reduced Siglec-10 expression, restoring macrophage and NK cell antitumor functions. In vivo and ex vivo, desialylation of stromal cells increased macrophage activation (CD11b+CD80+) and reduced immunosuppressive marker expression (CD206, PD-L1, Siglec-G) in lymphoid tissues, indicating sustained systemic anti-tumor immunity. Intratumoral NK cells exhibited high Siglec-G expression and impaired cytotoxicity, and granzyme B expression significantly increased with sialidase treatment of stromal cells. In an inflammatory tumor model, inflammatory tumor-conditioned MSCs (MSCiTCS) promoted metastasis and Siglec-G induction on NK cells and macrophages, both reversed by sialyltransferase inhibition, underscoring the effects of stromal modulation of innate immune cell function in inflammatory tumors.Conclusions Stromal cell sialylation modulates innate immune suppression in CRC via the sialic acid/Siglec axis. Targeting stromal sialylation restores NK cytotoxicity and macrophage activation, offering novel insights that may shape therapeutic strategies for reversing immunosuppression in stromal-rich tumors.

The tumour microenvironment (TME) comprises a complex interplay of tumour cells, nonmalignant cells (including endothelial, immune, and stromal cells), and secreted factors within the extracellular matrix (ECM). Immunosuppression within the TME significantly hinders the efficacy of cancer immunotherapies. Stromal-rich TMEs, characterised by an abundance of mesenchymal stromal cells (MSCs) and cancer-associated fibroblasts (CAFs), are particularly immunosuppressive and associated with poor responses to conventional and immune-based therapies. Glycans, carbohydrate structures on cell surfaces, are dynamically regulated during tumourigenesis and mediate crucial cell-cell communications through receptor-ligand interactions. Sialylation, the addition of sialic acids to glycans, forms sialoglycans that can engage inhibitory Siglec receptors expressed on immune cells and promote immunosuppressive signalling. Emerging evidence implicates aberrant sialylation in the TME as a key driver of immunosuppression. More recently, sialylation of stromal cells in the TME has been shown to suppress anti-tumor immunity. This review explores the role of sialylation within stromal-rich, immunosuppressive TMEs, focusing on how specific sialic acid/Siglec interactions dictate innate and adaptive immune responses. We discuss the potential of targeting glycoimmune checkpoints to overcome stromal-mediated resistance and enhance anti-tumour immunity.

Mesenchymal Stromal Cell derived extracellular vesicles (MSC-EVs) may retain the cancer targeting and immune privilege of MSCs. The immense potential MSC-EVs hold as tumour-targeted therapeutics warrants an understanding of potential adverse events to support clinical translation. This study aimed to determine whether MSC-EVs would elicit an immune response following administration in tumour-bearing immunocompetent animals. Secreted EVs were isolated from both human and murine bone marrow derived MSCs and characterized. hMSC-EVs or mMSC-EVs were administered intravenously into 4T1 breast tumour-bearing Balb/c mice or healthy controls. Tumour tissue, draining lymph nodes and spleens were harvested, dissociated into a single cell suspension and flow cytometry performed targeting T cells, myeloid derived suppressor cells (MDSCs), macrophages, dendritic cells and natural killer (NK) cells. The 4T1 model immune profile was first determined by comparing the spleen of tumour-bearing animals to healthy controls. T cells were increased in tumour-bearing animals (CD4+/CD25+ p=0.041; CD8+/CD25+ p=0.02). A significant elevation of GR-1+ MDSCs (p=0.002), CD11b+ macrophages (p=0.023) and CD11c+ dendritic cells (p=0.001) was also observed. In contrast, CD27+ NK cells were significantly decreased compared to the spleen of healthy animals (p=0.006). Collectively this data validated the immune profile and supported the determination of any changes in response to hMSC-EVs or mMSC-EVs administration. No significant activation of CD4+ (p=0.20) or CD8+ (p=0.57) T cells were seen in tumour tissue in both groups. The percentage of GR-1+ MDSCs (28% vs 27%, p=0.92), CD11b+, CD11c+ and CD27+ cells were similar regardless of EV origin. No significant changes in T cells, MDSCs, macrophages, dendritic or NK cells were observed in the lymph node or spleen of animals that received hMSC-EV versus mMSC-EVs. In conclusion, human MSC-EVs elicited no discernible immune response in mice, supporting the hypothesis that MSC-EVs retain the immune privilege of the secretory cell. This reinforces the therapeutic potential of MSC-EVs. ### Competing Interest Statement The authors have declared no competing interest.

Multiple myeloma (MM) is an incurable malignancy of clonal plasma cells. Incorporation of the monoclonal antibody daratumumab (dara) has improved treatment outcomes in newly diagnosed and relapsed/refractory MM (RRMM). The addition of low-dose, metronomic cyclophosphamide (cyclo) promotes dara-mediated NK cell cellular cytotoxicity and cellular phagocytosis in preclinical studies. We hypothesized that cyclo in combination with pomalidomide (pom), dexamethasone (dex) and dara could be effective in RRMM and we herein report the primary analysis from the multi-centre, Phase 1b Cyclophosphamide, Pomalidomide, Dexamethasone and Daratumumab (CPD-DARA) CTRIAL-IE-19-17(NCT04667663). Patients with RRMM after 2-5 prior lines, including a proteosome inhibitor and immunomodulatory agent, received 28-day cycles of cyclo 50mg orally daily, subcutaneous dara 1800 mg weekly for 2 cycles, fortnightly for 4 cycles and on day 1 thereafter, dex 40mg orally weekly (20mg if ≥70 years), and pom orally, started at 4mg on days 1-21 per cycle. Patients were enrolled by a 3+3 algorithm, with dose de-escalation and determination of the maximum tolerated dose (MTD) based on occurrence of dose limiting toxicities (DLTs) during cycle 1. Treatment continued until intolerance, progressive disease (PD) or death. The primary end-point was to determine the MTD of pom in combination with cyclo, dex and dara. Adverse events (AEs) were graded using the US National Cancer Institute Common Terminology Criteria for Adverse Events V5. Patient reported outcomes (PRO) were assessed using FACT-G and MyPOS surveys. Study was supported by research funding from Johnson & Johnson Innovative medicine Ireland, Bristol Myers Squibb, Friends of Cancer Trials Ireland, Health Research Board and Irish Cancer Society. 16 patients were enrolled. Median age was 67.5 years (range 46-77), 69% male,100% Caucasian, with a median 3 prior lines (1-5). 38% had received previous dara, 31% pom, 94% lenalidomide, 94% were double-class exposed, 38% triple-class exposed and 19% penta-class exposed. 38% had high-risk disease (ISS stage III or deletion of 17p, t(14;16) and/or t(4;14)). No DLTs occurred and MTD was determined as 4mg of pom. Median duration of exposure to therapy was 11.7 mons (0.2 - 33.8). At time of analysis, 14 patients had discontinued treatment (6 PD, 3 investigator decision, 4 AEs, of which 2 were deemed treatment-related, and 1 death) and 2 remain on treatment. Of the 14 patients, 8 completed study as per protocol and 6 have withdrawn (1 withdrew consent and 5 deaths). Treatment emergent adverse events (TEAEs) occurred in 100% (grade ≥3 94%). Haematologic grade ≥3 TEAEs included neutropenia (56%), lymphopenia (50%), anaemia (25%), leucopoenia (19%), and thrombocytopenia (19%). Other Grade ≥3 TEAEs occurring in ≥10% of participants were infection (19%), atrial fibrillation (13%), Covid-19 (13%), back pain (13%), diarrhoea (13%) and syncope (13%). Despite frequent grade ≥3 neutropenia, febrile neutropenia only occurred in 13% (all grade ≥3) and grade ≥3 pneumonia in 6%. Serious adverse events (SAEs) occurred in 81%, with infection and Covid-19 (19% each) the most common. One SAE resulted in death due to an acute myocardial infarction, unrelated to study treatment. The other 4 deaths were due to PD. MyPOS scores increased slightly from baseline to end of treatment (EOT), with a mean change from baseline (SD) of 4 (13.75). 75% of patients (95% CI 51-90) achieved ≥stable disease after cycle 6 and 50% (27-73) at EOT. Median time to response was 12.1 weeks (4.0-29.1). After 6 cycles, 38% were in ≥VGPR, 13% in CR, and 19% were MRD negative. Median progression free survival (mPFS) was 15.0 months (median follow-up 22.7). PFS was 75% (46-90) at 6 mons and 44% (18-67) at 18 mons. Overall survival (OS) was 88% (59-97) at 6 mons and 67% (41-86) at 18 mons. Patients with high-risk disease (n = 6) had less favourable outcomes, with a median PFS of 7 mons compared with 15 mons in non-high risk patients. CPD-DARA is an active regimen, with MRD-negative durable responses seen in RRMM. Safety is similar to other dara and pom-based combinations, with comparable rates of neutropenia and infection despite the addition of cyclo. CPD-DARA appears to be tolerable, with reassuring PRO data and few discontinuations due to AEs. These findings support further evaluation of CPD-DARA in larger trials as an active, cost-effective, regimen.

Corresponding Authors: Liam Grover and Thomas Ritter l.m.grover@bham.ac.uk and thomas.ritter@universityofgalway.ieIntroduction: Extracellular vesicles (EVs) are particles secreted from many cell types, containing lipids, proteins, and nucleic acids. Mesenchymal stromal cell‐derived EVs (MSC‐EVs) demonstrate similar therapeutic effects as their origin cells such as immunomodulation and tissue regeneration, while addressing safety concerns and other challenges associated to cell‐therapy (Rani et al. 2015, Wang et al. 2023). Delivering MSC‐EVs to the site of injury in a controlled and sustained manner may augment MSC‐EVs therapeutic efficacy. In this context, gellan gum fluid gel appears as a promising delivery system for MSC‐EVs which can extend the residence time of therapeutics on the cornea due to its shear‐dependent viscoelasticity, mucoadhesive feature and potential to bind to water. The solid‐liquid‐solid phase transition properties of the gellan gum fluid gel overcome the main challenges of commercial eyedrops like rapid clearance through lid overflow and drainage through the nasolacrimal duct (Chouhan et al. 2019). The aim of this study was to encapsulate MSC‐EVs in a gellan gum fluid gel and to investigate its release in‐vitro.Method: Human bone marrow MSCs were isolated, cultured in xeno‐free media, and characterized for surface biomarker expression using flow cytometry. MSC‐EVs were isolated from culture supernatants by size exclusion chromatography and further characterized following MISEV guidelines for size distribution, zeta potential, morphology, and surface biomarkers profile, respectively. Gellan gum fluid gels were created by cooling a solution of low acyl gellan gum in a shear field, with sodium chloride as crosslinker under a constant mechanical separation. The gellan gum fluid gel was further characterized using shear and dynamic oscillatory techniques, measuring the material viscosity and viscoelasticity. MSC‐EVs were encapsulated in the gellan gum fluid gel, followed by the analysis of their release profile from the gellan gum fluid gel at 0, 1, 2, 3, 4, 5, and 6hr.Results: MSCs showed positive surface biomarker expression for CD90, CD73, and CD44, and negative for CD45, CD11b, and HLA‐DR. MSC‐EVs had spherical bilayer morphology with a size of approximately 83 nm and displayed a slight negative surface charge. MSC‐EVs were positive for surface biomarkers CD9, CD63, and CD81 analysed by flow cytometry. The Gellan gum fluid gels were shown to act as solids at rest, improving retention on the eye, but as fluids when a force is applied, easing application and distribution on the ocular surface through blinking. At lower strains, the gellan gum fluid gel viscoelasticity showed that the G’ (storage modulus) was higher than G” (viscous modulus) states in the linear viscoelastic region. Conversely, in higher strains the G’ declined to reach lower values than for the G”, resulting into a liquid phase system.The cumulative release profile of the MSC‐EVs from the gellan gum fluid gels showed a controlled release profile through 6 hr investigation.Conclusion: Altogether, these results evidenced that the physical and release properties of the MSC‐EV laden gellan gum fluid gels demonstrate their potential as ocular healing materials, necessitating investigation of the therapeutic efficacy of the released‐MSC‐EVs in 2D and 3D in‐vitro studies of corneal injury.ReferencesChouhan G, Moakes RJA, Esmaeili M, et al. (2019): A self‐healing hydrogel eye drop for the sustained delivery of decorin to prevent corneal scarring. Biomaterials 210: 41–50.Rani S, Ryan AE, Griffin MD & Ritter T (2015): Mesenchymal Stem Cell‐derived Extracellular Vesicles: Toward Cell‐free Therapeutic Applications. Molecular Therapy 23: 812–823.Wang J, Donohoe E, Canning A, Moosavizadeh S, Buckley F, Brennan MÁ, Ryan AE & Ritter T (2023): Immunomodulatory function of licensed human bone marrow mesenchymal stromal cell‐derived apoptotic bodies. International Immunopharmacology 125: 111096.

It is well established that the mesenchymal stromal cell (MSC) therapeutic potency can be enhanced by cytokine pre-activation or licensing. However, its effects on therapeutic efficacy of small extracellular vesicles (MSC-sEV) have not yet been well established. Here we report on two different cytokine licensing strategies, using either a pro-inflammatory or anti-inflammatory cytokine and evaluate their therapeutic potency in vitro and in a preclinical model of corneal chemical burn. BALB/c MSCs were cultured with no supplement, recombinant IFNγ, or recombinant TGFβ1 for 72 h. sEV, sEVIFNγ, and sEVTGFβ were then isolated from conditioned medium of parental cells by a combination of ultrafiltration and size exclusion chromatography. Following isolation MSC-sEV were thoroughly characterized for size, marker expression and therapeutic efficacy. To evaluate their immunomodulatory capacity, both naïve and licensed MSC-sEV were tested in in vitro macrophage and T cell assays and in a preclinical corneal injury model. Relative to unlicensed sEV, sEVIFNγ exhibited increased expression of MHC I and PD-L1 on their surface, whereas sEVTGFβ expressed higher levels of CD44, CD29, and CD73. For immunomodulatory capacity, only sEVTGFβ was found to reduce macrophage expression of MHC II and CD80 and induced the secretion of anti-inflammatory macrophage cytokines. sEVTGFβ were also found to increase Treg expansion and FOXP3 expression. Given the superior efficacy observed of sEVTGFβ in vitro, this product was evaluated in a preclinical mouse model of corneal chemical burn. sEVTGFβ were applied either topically (day 0, 1, and 3) or subconjunctivally (day 0, and 3), and mice were monitored for 14 days. sEVTGFβ ameliorated burn-induced structural damage and accelerated restoration of normal corneal thickness, compared to PBS-treated controls. sEVTGFβ also resulted in reduced inflammatory mediators (IL-1β, iNOS) and minimised levels of fibrosis-associated collagen in the cornea. Mice that received subconjunctival, but not topical, administration of sEVTGFβ exhibited regulatory immune cell profiles with reduced pro-inflammatory- macrophages, increased anti-inflammatory macrophages, and restored Treg function and balance of the Treg/Th17 axis. Overall, IFNγ and TGFβ licensing strategies were found to yield unique MSC-sEV phenotypes that can modulate inflammation differentially in vitro and in a corneal chemical burn model. This work found sEVTGFβ to represent a promising cell-free therapy for the treatment of corneal chemical burns.

ObjectiveOsteoarthritis (OA) is a widespread and debilitating joint disease characterized by synovial inflammation, cartilage degeneration, and chronic joint pain. Mesenchymal stromal cells (MSCs) have shown therapeutic efficacy for many diseases with a strong inflammatory profile, including OA. However, the disease-specific mechanisms of action underpinning the effects of post-local MSC delivery remain unaddressed. In this study, we aimed to characterize the disease-induced profile of MSCs following exposure to the in vivo osteoarthritis environment.MethodsMurine syngeneic GFP + bone marrow-derived MSCs (BM-MSCs) were delivered via intra-articular injection in a mouse collagenase-induced osteoarthritis (CIOA) model (n = 8). BM-MSCs were retrieved by cell sorting on days 14 and 56, following whole mouse knee digestions. The retrieved cells were expanded in culture and characterized based on their phenotype, immunomodulatory effects on lymphocytes and macrophages, and transcriptomic profile.ResultsRetrieved BM-MSCs (1.33%) had minimal effects on lymphocyte proliferation but induced macrophage anti-inflammatory activity. Surviving retrieved BM-MSCs activated various pathways, with their secretome impacting immune system regulation and extracellular matrix organization, correlating with the disease stage. Data comparing the transcriptomic profiles of retrieved and in vitro-licensed BM-MSCs suggested a chondroprogenitor profile and identified BRINP3 as a novel factor in MSC function for potential OA modulation.ConclusionThe beneficial effects of BM-MSCs in OA post-local delivery could be attributed to a specific subset of cells able to resist the micro-inflammatory milieu and contribute to cartilage healing and suppression of associated synovial inflammation. Furthermore, data suggest a paradigm of environmentally guided plasticity associated with MSCs upon local delivery in both early and late OA.

Mesenchymal stromal cells (MSCs) possess strong immunomodulatory properties, making them attractive candidates for regenerative medicine and immune-related therapies. Pre-activation, or licensing, of MSCs with cytokines such as interferon-gamma (IFN-γ) and transforming growth factor-beta 1 (TGF-β1) has been shown to enhance their immunosuppressive efficacy. Recent attention has turned to extracellular vesicles (EVs) released by licensed MSCs as a cell-free therapeutic alternative. Small EVs were isolated from MSCs licensed with a combination of IFN-γ and TGF-β1. These EVs were characterized according to standardized criteria. Their immunomodulatory effects were assessed in vitro using two human immune models: a THP-1-derived macrophage polarization system and a peripheral blood mononuclear cell (PBMC) co-culture assay. Pro/anti-inflammatory molecules secretion, T cell proliferation, and regulatory T cell induction were quantified. Dimensionality reduction using t-distributed stochastic neighbor embedding (t-SNE) was applied to multiparametric flow cytometry data for immune profiling. In addition, publicly available transcriptomic datasets (GSE122091 and GSE46019) were analyzed to identify differentially expressed genes (DEGs) in IFN-γ– and TGF-β1–licensed MSCs, providing insight into potential molecular drivers of EV-mediated immunoregulation. Licensed EVs significantly inhibited pro-inflammatory THP-1 macrophage activation and promoted an anti-inflammatory phenotype, with reduced secretion of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), increased IL-10 production, and decreased nitric oxide (NO) levels.. Compared to EVs from non-licensed MSCs, licensed EVs induced a greater proportion of regulatory T cells and exhibited enhanced suppression of allogeneic T cell proliferation. t-SNE analysis revealed a distinct immunoregulatory signature induced by licensed EVs, characterized by the emergence of a non-proliferative lymphocyte subset with elevated co-expression of CD4, CD25, and FOXP3. Transcriptomic analysis further revealed seven overlapping DEGs between IFN-γ– and TGF-β1–licensed MSCs, including both upregulated (GPR68, LIMK2, LIPG) and downregulated (EFNA5, PRKG1, DCLK1, TRIM2) genes, several of which are functionally implicated in EV-mediated immune regulation. Small EVs derived from IFN-γ and TGF-β1-licensed MSCs exhibit demonstrate dose-dependent immunomodulatory trends in vitro, with enhanced effects observed at higher concentrations.. These findings suggest their potential utility in modulating both innate and adaptive immune responses, warranting further investigation for their application as a cell-free therapeutic strategy in immune-mediated conditions.

BACKGROUND:Mesenchymal stromal cell (MSC) apoptosis is essential for their therapeutic effects, including immunomodulation. Previous studies have shown that MSC-derived apoptotic bodies (ApoBDs) also possess immunomodulatory properties. However, compared to small extracellular vesicles, the preparation, characterization, and biological properties of ApoBDs remain underexplored. RESULTS:ApoBDs were isolated from the conditioned medium of staurosporine-induced apoptotic human MSCs and categorized into large (∼700 nm) and small (∼500 nm) groups. Both types expressed CD90, CD44, and CD73, with low levels of PD-L1, CD11b, and HLA-DR, mirroring their parental MSCs. Functional assays revealed that both ApoBDs inhibited allogeneic T-cell proliferation, with large ApoBDs demonstrating superior efficacy. In macrophage co-culture experiments, both ApoBDs polarized M1 macrophages toward an M2-like phenotype, with large ApoBDs more effectively upregulating CD163 expression. Additionally, both ApoBDs suppressed the proliferation of murine primary T cells. Furthermore, large ApoBDs exhibited enhanced macrophage uptake, as confirmed by flow cytometry and immunocytochemistry. Importantly, no cytotoxicity was observed for either ApoBD type following staurosporine treatment. CONCLUSIONS:Staurosporine-induced ApoBDs are non-cytotoxic and exhibit significant immunomodulatory potential in vitro. Large ApoBDs are more effective than small ApoBDs in T-cell suppression and M2 macrophage polarization, suggesting their potential as an alternative to MSC-based therapies in future studies.

Cytokine(s) pre-activation/licensing is an effective way to enhance the immunomodulatory potency of mesenchymal stromal cells (MSCs). Currently, IFN-gamma licensing received the most attention in comparison with other cytokines. After licensing human bone marrow-derived MSCs with pro-/anti-infammatory cytokines IFN-gamma, IL-1 beta, TNF-alpha, TGF-beta 1 alone or in combination, the in vitro immunomodulatory potency of these MSCs was studied by incubating with allogeneic T cells and macrophage-like THP-1 cells. In addition, immunomodulation-related molecules fltered by bioinformatics, complement 1 subcomponent (C1s), and interferon-induced GTP-binding protein Mx2 (MX2), were studied to verify whether to refect the immunomodulatory potency. Herein, we reported that different cytokines cause different effects on the function of MSC. While TGF-beta 1 licensing enhances the capacity of MSCs to induce T cells with an immunosuppressive phenotype, IFN-gamma-licensing strengthens the inhibitory effect of MSC on T cell proliferation. Both TGF-beta 1 and IFN-gamma licensing can enhance the effect of MSC on reducing the expression of pro-infammatory cytokines by M1 macrophagelike THP-1 cells. Interestingly, IFN-gamma upregulates potential potency markers extracellular C1s and kynurenine (KYN) and intracellular MX2. These 3 molecules have the potential to refect mesenchymal stromal cell immunomodulatory potency. In addition, we reported that there is a synergistic effect of TGF-beta 1 and IFN-gamma in immunomodulation.

Background: Public and patient involvement (PPI) is described as research carried out "with" or "by" members of the public, rather than "to", "about" or "for" them, improving quality and relevance of research. While PPI panels are more commonly associated with clinical research, we describe here the novel integration of a PPI panel in a multidisciplinary translational research group focused on discovery of immunotherapeutics in colorectal cancer (CRC). Methods: A member of the research group undertook training courses in PPI. Particulars including panel duration, budget and number of participants were defined. The local PPI Ignite office was consulted in relation to remuneration, safeguarding, and handling conflict and distress. Documentation including a recruitment poster and person specification was created. The poster was shared through social media, patient advocacy groups and displayed in patient waiting areas. Contact was made with respondents and meetings organised. Results: A PPI panel to contribute in a laboratory setting has been successfully established by the Galway Academic Intestinal Network (GAIN). Specific definition of the particulars of the project was crucial. The scientist/clinician multidisciplinary collaborative nature of our group proved invaluable for conceptualisation and recruitment. We note a preponderance of female engagement and direct patient experience among respondents. Conclusions: PPI contribution greatly enhances research. We report our experience of the feasibility of establishment of a novel PPI panel and its engagement with a multidisciplinary translational research group.

There is growing recognition of the importance of sialylation as a critical post translational modification in cancer. In this article we review the role of increased cell surface sialylation (hypersialylation) in Multiple Myeloma as it relates to cellular trafficking and immune evasion. Knowledge of the specific effects of sialic acid on cell trafficking machinery and modulation of immune cell interactions will identify opportunities for therapeutic interventions. The available evidence indicates that hypersialylation facilitates disease progression and negatively impacts on response to treatment and overall survival. Further research is required to fully elucidate the mechanisms through which hypersialylation influences disease biology and therapy resistance with the ultimate goal of developing new treatment approaches to improve the outcomes of patients with Multiple Myeloma.