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Importance Accurate classification and reliability in assessment for lesions of hidradenitis suppurativa (HS) by investigators is critical to the determination of responder status and to overall data quality in clinical trials. Objective To establish consensus-based morphological definitions of HS lesions and guidance statements that standardize investigator lesion assessments for implementation in clinical trials. Evidence Review Health professionals (primarily dermatologists) with expertise in the measurement of HS disease activity as well as novice raters completed a preliminary questionnaire in which participants were asked to assess images of HS lesions and provide qualitative feedback on their decision making. Based on this feedback, detailed morphologic definitions for lesions and guidance statements that standardize lesion assessments were formulated and presented for consensus voting in 2 electronic Delphi surveys. A virtual group discussion after round 1 supported participants in round 2 voting. Findings Response rates were 84.7% (50 of 59), 86.0% (43 of 50), and 90.9% (40 of 44) in the preliminary, electronic Delphi round 1, and electronic Delphi round 2 surveys, respectively. Morphological definitions for 11 lesion types achieved the prespecified 70% consensus threshold, with 9 definitions reaching at least 90% agreement. After 2 electronic Delphi rounds, 16 of 18 guidance statements achieved the prespecified consensus threshold, with 13 statements receiving endorsement from more than 80% of participants. Two guidance statements related to assessment of tunneled plaques with multiple openings and assessment of scalp lesions failed to reach consensus. Conclusions and Relevance Common morphologic definitions and guidance that standardize assessment of HS lesions can be implemented in clinical trial protocols and investigator trainings with the goals of improving accuracy and reliability of investigator ratings.

ABSTRACT Central venous catheters (CVCs) are a cornerstone of hematopoietic stem cell transplantation (HSCT), facilitating the delivery of chemotherapy, parenteral nutrition, medications, and blood products. Despite CVCs’ essential role, prolonged use can lead to complications such as increased risk of infection, thrombosis, mechanical issues, and psychosocial burden. However, the timing of CVC removal remains highly variable across institutions. Additionally, there are no standardized guidelines to balance the benefits of extended access against the risks of prolonged use. This narrative review examines the existing literature on CVC management post‐HSCT, highlighting key factors influencing the removal timing, such as patient characteristics, disease‐specific considerations, and institutional practices. The review emphasizes the urgent need for multi‐institutional research and standardized protocols to improve outcomes, reduce complications, and enhance the quality of care for HSCT patients.

Collaboration between biobanks and research teams is essential for advancing scientific research, particularly in studies involving human subjects; however, various challenges can hinder success. We shed light on key obstacles and challenges encountered during a partnership between a clinical trial and an institutional biobank at a pediatric hospital. In aiming to recruit pediatric biobank participants for a genomic clinical research study, key challenges included low-yield recruitment tactics, independent operations and structures of the biobank and research teams, and transition to a new biobank model resulting in struggles with participant reengagement. This article explores some of the obstacles experienced by the research and biobanks teams, while providing key lessons aimed at guiding others in planning future collaborations for trial recruitment, enrollment, and implementation. We also highlight the significant benefits that can arise when biobanks and research teams work together strategically.

Introduction Tobacco use is the most significant modifiable risk factor for adverse health outcomes, and early research indicates there are also significant harms associated with vaping. National targets aim to reduce smoking and vaping during pregnancy for Aboriginal and Torres Strait Islander people. While most Aboriginal and Torres Strait Islander people want to quit, cessation is frequently attempted without support, increasing the chance of relapse. Group-based smoking cessation programmes increase quit success by 50%–130% in the general population; however, they have never been evaluated in Aboriginal and/or Torres Strait Islander communities. Methods and analysis The Gulibaa study is an Indigenous-led and community-embedded project that will co-design, implement and evaluate a group-based model of care to support Aboriginal and Torres Strait Islander women to be smoke- and vape-free. Staff of Health Services in New South Wales, Australia, will receive training to deliver a face-to-face group-based smoking and vaping cessation intervention. Aboriginal and/or Torres Strait Islander people who identify as a woman or non-binary, are pregnant or of reproductive age (16 to 49 years), currently smoke or vape at least once per day and are willing to attend the programme are eligible to participate. Up to 500 participants will be recruited. A mixed method evaluation approach will be implemented guided by the RE-AIM framework. Outcomes will include intervention reach, intervention effectiveness (determined primarily by self-reported 7-day point prevalence abstinence at 6 months follow-up), acceptability and feasibility of the intervention, programme fidelity and maintenance and cost effectiveness. Ethics and dissemination Embedding culturally safe support to quit during pregnancy can result in improved outcomes for both mother and child and immediately improve intergenerational health and well-being. Ethics approval has been provided by the Aboriginal Health and Medical Research Council and the University of Newcastle. Study findings will be disseminated to Aboriginal and Torres Strait Islander communities in ways that are meaningful to them, as well as through Aboriginal health services, key national bodies, relevant state and federal government departments. Trial registration number ACTRN12625001050448.

Src homology 2-domain containing protein tyrosine phosphatase 2 (SHP2), encoded by the Ptpn11 gene (Tyrosine-protein phosphatase non-receptor type 11), is a key downstream effector of PD-1/PD-L1 signaling and is likely important, in addition to immune modulation, in tumor development and vascular homeostasis. SHP2 conveys PD-1 mediated inhibitory signaling in T cells, and is emerging as a therapeutic target. Importantly, there is an association between immune checkpoint inhibitors (ICIs), immune-related adverse events (irAEs), and cardiovascular complications, underscoring the need to understand SHP2’s role in these processes. This review aims to summarize current knowledge on SHP2/PTPN11 biology, its role in immune regulation, cancer progression, and vascular homeostasis, and to discuss emerging therapeutic strategies targeting this pathway. The concept of using SHP2 inhibitors with immune checkpoint inhibitors (ICIs) is being investigated to address ICI resistance and to improve anti-tumor efficacy substantially. SHP2 is also being studied in non-cancer cell contexts, and signaling responses can differ by large magnitudes depending on the biological context and stimuli. Under normal circumstances, SHP2 promotes vascular homeostasis in endothelial cells (ECs) and myeloid cells and inhibits inflammation, and the reduction in SHP2 activity by oxidative stress, such as in atherosclerosis or diabetes, upregulates inflammation. In contrast, in response to radiation, the fibrotic response and subsequent lung injury were increased by endothelial SHP2 induction via Notch-Jag1 signaling. Vascular smooth muscle cells SHP2 act as a pro-atherogenic effector by enhancing ERK/MAPK signaling, and the upregulation of mitochondria localized SHP2 can also induce cellular senescence-associated inflammation by upregulating mitochondrial reactive oxygen species. Taken together, the two opposite signaling effects of SHP2 suggest that both the immune and vascular system responses appear to be more modulated by the redox, cell, and compartment-specific signaling of SHP2. More studies are needed for mitigating cardiovascular toxicity to patients, particularly with ICI-based treatment regimens.

Abstract Description Therapies targeting the PD-1/PD-L1 axis are among the leading treatments of cancer, but only a minority of patients benefit. Many therapies focus on preventing PD-L1 from binding to its receptor, PD-1, but do not address PD-L1’s ability to be recycled to the cell surface and any intrinsic functions it may possess. Our lab has developed an antibody (H1A) that binds to PD-L1 and prevents its association with a stabilizing protein, CMTM6, therefore targeting it for lysosomal degradation. Consequently, H1A limits any PD-L1 intrinsic function while also decreasing interactions with PD-1. Here, we use human-derived immune cells to test H1A’s effect on immune responses through flow cytometry, multiplex screening, and cytotoxicity assays. Additionally, we have developed a humanized PD-1/PD-L1 mouse model that allows us to test H1A’s effect on tumor growth inhibition in an immunocompetent host. Our results show that H1A specifically targets human myeloid cells, resulting in increased co-stimulation, antigen presentation, and cytokine secretion. H1A demonstrated enhanced T cell cytotoxicity in a whole PBMC culture. Finally, H1A resulted in greater tumor growth inhibition and survival in our in vivo tumor models. This work highlights the importance of targeting beyond PD-1/PD-L1 ligation and that myeloid cells are instrumental to enhancing the immune response against cancer. H1A is emerging as a new immunotherapy tool to target PD-L1 and CMTM6 in myeloid cells for treatment of cancers. Funding Sources NIH R01 92389022; NIH T32 AI170478; Mayo Clinic Graduate School of Biomedical Sciences Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Abstract Description A durable T cell immunity against cancer is dependent on a continually refilling of effector CD8+ T cells. Thymic output has been correlated with favorable prognosis in cancer patients of advanced ages, suggesting thymus is an important source for refilling T cells that are capable of controlling cancer progression in the periphery. However, it remains unclear how PD-1 signals regulate the cytotoxic potential of CD8+ T cells in thymus before they egress to the periphery to establish durable anti-tumor immunity. Here we report PD-1 signaling prelimits thymic single positive (SP) CD8+ T cells to acquire cytotoxic potential by downregulating Gzmb and Nkg7, which are required for CD8+ T cell-mediated cytotoxicity. Unexpectedly, we found the absence of Pdcd1 also led to upregulation of Tox and Tim3 in thymic SP CD8+ T cells, thereby pre-programming these cells for exhaustion within the tumor. Thus, the absence of PD-1 signals in CD8+ T cells only partially delayed tumor growth in peripheral tissues. To improve therapeutic effects of PD-1 inhibition, we observed that tumor growth in CD8-specific Pdcd1 conditional knockout mice was further suppressed by treatment with a PD-L1 antibody that blocks PD-L1 and CD80 interaction. Our results imply that PD-1 inhibition promotes the expansion of effector cytotoxic CD8+ T cells but also retains T cell exhaustion potential, which can be mitigated by PD-L1 blockade that allows more CD80 to provide costimulatory signals to T cells via CD28. Funding Sources NCI R01CA256927 NCI R01CA261932 NCI P30CA15083 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Abstract Description The efficacy of ICI and T cell-based therapies is dependent on sufficient killing of tumor cells by T cells. Thus, it’s critical for effector T cells to maintain their function and overcome metabolic stress within the tumor microenvironment. Our previous work in human resilient CD8+ T cells identified malic enzyme 1 (ME1) as a key enzyme that augments effector CD8+ T cells’ metabolic and functional fitness via increased ATP production and curbed ROS production. To further study ME1’s role in promoting CD8+ T cell resilience in vivo, we produced CD8-specific ME1 conditional knockout and transgenic (ME1 Tg) mouse models. In MC38, ME1 was upregulated in CD8+ T cells in TILs compared to those in spleen and ME1 loss in CD8+ T cells abrogated tumor responses to ICI. In ME1 Tg mice, MC38 had reduced tumor growth, while B16F10 tumors were sensitized to ICI. We observed lower ROS and increased lipid content in CD8+ T cells in the TILs of ME1 Tg mice, underscoring ME1’s role in activating alternative metabolic pathways to fuel mitochondrial respiration while keeping ROS in check. The association of ME1 with 6PGD, a key enzyme in the pentose phosphate pathway (PPP), implies its regulation of redox homeostasis in CD8+ T cells. Importantly, ME1 overexpression in TILs dramatically improved the efficacy of TIL therapy in treatment of established tumors. Overall, ME1 upholds T cell resilience in tumor tissues and provides a new therapeutic target to improve the efficacy of TIL therapy. Funding Sources This work was supported by the Mayo Clinic Center for Biomedical Discovery (to H.D.); the Mayo Clinic Cancer Center’s David F. and Margaret T. Grohne Cancer Immunology and Immunotherapy program (to H.D.); R01 AI095239 (to H.D.), R01 CA200551 (to H.D. and S.S.P.), and R01 CA256927 (to H.D.). Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

Abstract Description Background Primary sclerosing cholangitis (PSC) is an immune-mediated liver disease characterized by chronic inflammation and fibrosis of the bile ducts. The primary cells impacted in PSC are bile duct epithelial cells called cholangiocytes. Mucosal associated invariant T (MAIT) cells are enriched in human liver and associated with fibrosis. We hypothesize that cholangiocyte-activated MAIT cells drive fibrosis in PSC. Results Flow cytometry of PSC patient bile duct brushings show that 30% of T cells are MAIT cells, suggesting their co-existence with cholangiocytes within the peri-biliary environment. Re-analysis of single cell RNA sequencing data of PSC patient cholangiocyte organoids reveals upregulation of MR1 gene, indicating their enhanced ability to activate MAIT cells. Proteomics of human MAIT cells identify the expression of multiple profibrotic factors including secreted protein acidic and rich in cysteine (SPARC). Flow cytometry of TCR-activated MAIT cells show a significant and dose-dependent increase in a SPARClow MAIT population, indicating release of SPARC. Re-analysis of Olink proteomics on supernatant of PSC cholangiocyte organoids show IL-17C secretion. IL-17C treatment of TCR-activated MAIT cells result in significant upregulation of SPARC gene. Conclusion MAIT cells secrete profibrogenic mediators and MAIT cell profibrogenicity is enhanced by IL-17C, a novel cytokine released by cholangiocytes in PSC. Funding Sources C-SIG P30DK084567 Topic Categories Mucosal and Regional Immunology (MUC)