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Selectins are cell adhesion proteins discovered in the 1980s. As C-type lectins, selectins contain an essential calcium ion in the ligand-binding pocket and recognize the isomeric tetrasaccharides sialyl Lewis x (sLe x ) and sialyl Lewis a (sLe a ). Three selectins, E-selectin, P-selectin, and L-selectin, play distinct, complementary roles in inflammation, hematopoiesis, and tumor biology. They have been implicated in the pathology of diverse inflammatory disorders, and several selectin antagonists have been tested clinically. E-selectin plays a unique role in leukocyte activation, making it an attractive target for intervention, for example, in sickle cell disease (SCD). This review summarizes selectin biology and pathology, structure and ligand binding, and selectin antagonists that have reached clinical testing with an emphasis on E-selectin., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: John M. Peterson declare(s) employment, a patent, stock/stock options and travel from GlycoMimetics, Inc. Edwin P. Rock declare(s) employment, stock/stock options and travel from GlycoMimetics, Inc. John L. Magnani declare(s) personal fees, employment and stock/stock options from GlycoMimetics, Inc. Theodore A. Smith declare(s) employment, a patent and stock/stock options from GlycoMimetics, Inc. Intellectual property info: All authors are currently or were recently employees of GlycoMimetics Inc. As such, we have been involved in the discovery and development of the E-selectin antagonists uproleselan and GMI-1687, as well as the pan-selectin antagonist rivipansel, which are described in this manuscript. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Peterson et al.)

Background: Patient survival in advanced/metastatic melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC) has improved with immune checkpoint inhibitors (ICI). Biomarkers' role in prognosis and treatment has been limited by conflicting trial results., Methods: This retrospective, observational study analyzed baseline demographic, clinical, laboratory, and treatment data versus outcomes of The US Oncology Network adult outpatients. Patients with advanced/metastatic melanoma, NSCLC, or RCC treated between January 1, 2015 and November 30, 2020 were given ICI monotherapy or combination therapy with ipilimumab, pembrolizumab, nivolumab, or atezolizumab. Treatment outcomes (overall survival [OS], time to treatment discontinuation, time to next treatment) were followed longitudinally until May 31, 2021, last patient record, or date of death. Baseline blood cell counts, including absolute monocyte count (AMC), absolute lymphocyte count (ALC), monocyte-to-lymphocyte ratio (MLR), absolute neutrophil count (ANC), and eosinophil count, were subdivided into quintiles for univariate and multivariable Cox regression analyses., Results: Data from 18,186 patients with advanced/metastatic melanoma (n = 3314), NSCLC (n = 12,416), and RCC (n = 2456) were analyzed. Better OS correlated with increased baseline serum albumin concentration, increased eosinophil and lymphocyte counts, and Western United States physician practice location. Decreased OS correlated with increased AMC, MLR, ANC, age, and worse Eastern Cooperative Oncology Group performance status., Conclusions: To our knowledge, this study is the largest to date to associate baseline survival indicators and outcomes in outpatients with advanced/metastatic melanoma, NSCLC, or RCC and receiving ICIs. Results may inform disease-specific prognostic models and help providers identify patients most likely to benefit from ICI therapy., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Sepsis, a heterogeneous clinical syndrome, features a systemic inflammatory response to tissue injury or infection, followed by a state of reduced immune responsiveness. Measurable alterations occur in both the innate and adaptive immune systems. Immunoparalysis, an immunosuppressed state, associates with worsened outcomes, including multiple organ dysfunction syndrome, secondary infections, and increased mortality. Multiple immune markers to identify sepsis immunoparalysis have been proposed, and some might offer clinical utility. Sepsis immunoparalysis is characterized by reduced lymphocyte numbers and downregulation of class II human leukocyte antigens (HLA) on innate immune monocytes. Class II HLA proteins present peptide antigens for recognition by and activation of antigen-specific T lymphocytes. One monocyte class II protein, mHLA-DR, can be measured by flow cytometry. Downregulated mHLA-DR indicates reduced monocyte responsiveness, as measured by ex-vivo cytokine production in response to endotoxin stimulation. Our literature survey reveals low mHLA-DR expression on peripheral blood monocytes correlates with increased risks for infection and death. For mHLA-DR, 15,000 antibodies/cell appears clinically acceptable as the lower limit of immunocompetence. Values less than 15,000 antibodies/cell are correlated with sepsis severity; and values at or less than 8000 antibodies/cell are identified as severe immunoparalysis. Several experimental immunotherapies have been evaluated for reversal of sepsis immunoparalysis. In particular, sargramostim, a recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF), has demonstrated clinical benefit by reducing hospitalization duration and lowering secondary infection risk. Lowered infection risk correlates with increased mHLA-DR expression on peripheral blood monocytes in these patients. Although mHLA-DR has shown promising utility for identifying sepsis immunoparalysis, absence of a standardized, analytically validated method has thus far prevented widespread adoption. A clinically useful approach for patient inclusion and identification of clinically correlated output parameters could address the persistent high unmet medical need for effective targeted therapies in sepsis., Competing Interests: IJ is an employee of and has stock options for Partner Therapeutics, Inc. WPC is the owner of Walt Carney Biomarkers Consulting and a paid consultant for Partner Therapeutics, Inc. At the time of the drafting of this manuscript, EPR was an employee of Partner Therapeutics, Inc. and has stock options., (Copyright © 2023 Joshi, Carney and Rock.)

Introduction: Endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF), identified by its ability to support differentiation of hematopoietic cells into several types of myeloid cells, is now known to support maturation and maintain the metabolic capacity of mononuclear phagocytes including monocytes, macrophages, and dendritic cells. These cells sense and attack potential pathogens, present antigens to adaptive immune cells, and recruit other immune cells. Recombinant human (rhu) GM-CSF (e.g., sargramostim [glycosylated, yeast-derived rhu GM-CSF]) has immune modulating properties and can restore the normal function of mononuclear phagocytes rendered dysfunctional by deficient or insufficient endogenous GM-CSF., Methods: We reviewed the emerging biologic and cellular effects of GM-CSF. Experts in clinical disease areas caused by deficient or insufficient endogenous GM-CSF examined the role of GM-CSF in mononuclear phagocyte disorders including autoimmune pulmonary alveolar proteinosis (aPAP), diverse infections (including COVID-19), wound healing, and anti-cancer immune checkpoint inhibitor therapy., Results: We discuss emerging data for GM-CSF biology including the positive effects on mitochondrial function and cell metabolism, augmentation of phagocytosis and efferocytosis, and immune cell modulation. We further address how giving exogenous rhu GM-CSF may control or treat mononuclear phagocyte dysfunction disorders caused or exacerbated by GM-CSF deficiency or insufficiency. We discuss how rhu GM-CSF may augment the anti-cancer effects of immune checkpoint inhibitor immunotherapy as well as ameliorate immune-related adverse events., Discussion: We identify research gaps, opportunities, and the concept that rhu GM-CSF, by supporting and restoring the metabolic capacity and function of mononuclear phagocytes, can have significant therapeutic effects. rhu GM-CSF (e.g., sargramostim) might ameliorate multiple diseases of GM-CSF deficiency or insufficiency and address a high unmet medical need., Competing Interests: HL is a paid consultant to Partner Therapeutics and has stock options. KP, TB, and CR, are employees of Partner Therapeutics and have stock options. ER at the time of drafting of this manuscript was an employee of Partner Therapeutics and has stock options. TW, EB, MD, RP, and RG received funds from Partner Therapeutics within the past 3 years, but none in relation to this publication. HL is a paid consultant to Pluri-Biotech, Inc. TW acknowledges support from Savara, Kiniksa, Kinevant (for participation on a DSMB or advisory board), the PAP Foundation (serves as the vice president and clinical director of the PAP Foundation) and is a paid consultant to IQVIA. EL acknowledges funding from the NIH, myCME, is a paid consultant to Guidepoint Global, and received support for travel from the PAP Foundation. EB acknowledges support from Genentech, Novartis, and Lilly, and received funds from Apexigen, Shionogi, Bristol Myers Squibb, Nektar, Instilbio, and Xilio for consulting within the past 3 years. MD received funds from Neolukin Therapeutics (and has stock options), Moderna, Aditum, OREC, Tillotts Pharma, SQZ Biotech, AzurRx, and Mallinckrodt for consulting within the past 3 years, and acknowledges support from UpToDate, Sandoz Academy, Experts at Your Fingertips, and WebMD. DA acknowledges funding from the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. RP acknowledges support to his institution from the US Department of Veterans Affairs and the NHLBI. RG is a consultant to NexImmune Inc., Ananexa Pharma Ascentage Pharm Group, Antengene Biotech LLC, and a Medical Director within FFF Enterprises Inc. and AZAC Inc. RG serves on the Board of Directors of the Russian Foundation for Cancer Research Support and is on the Scientific Advisory Board of StemRad Ltd., (Copyright © 2023 Lazarus, Pitts, Wang, Lee, Buchbinder, Dougan, Armstrong, Paine, Ragsdale, Boyd, Rock and Gale.)

Several therapeutic monoclonal antibodies (mAbs), including those targeting epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER2), and CD20, mediate fragment crystallizable gamma receptor (FcγR)-dependent activities as part of their mechanism of action. These activities include induction of antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), which are innate immune mechanisms of cancer cell elimination. FcγRs are distinguished by their affinity for the Fc fragment, cell distribution, and type of immune response they induce. Activating FcγRIIIa (CD16A) on natural killer cells plays a crucial role in mediating ADCC, and activating FcγRIIa (CD32A) and FcγRIIIa on macrophages are important for mediating ADCP. Polymorphisms in FcγRIIIa and FcγRIIa generate variants that bind to the Fc portion of antibodies with different affinities. This results in differential FcγR-mediated activities associated with differential therapeutic outcomes across multiple clinical settings, from early stage to metastatic disease, in patients with HER2+ breast cancer treated with the anti-HER2 mAb trastuzumab. Trastuzumab has, nonetheless, revolutionized HER2+ breast cancer treatment, and several HER2-directed mAbs have been developed using Fc glyco-engineering or Fc protein-engineering to enhance FcγR-mediated functions. An example of an approved anti-HER2 Fc-engineered chimeric mAb is margetuximab, which targets the same epitope as trastuzumab, but features five amino acid substitutions in the IgG 1 Fc domain that were deliberately introduced to increase binding to activating FcγRIIIa and decrease binding to inhibitory FcγRIIb (CD32B). Margetuximab enhances Fc-dependent ADCC in vitro more potently than the combination of pertuzumab (another approved mAb directed against an alternate HER2 epitope) and trastuzumab. Margetuximab administration also enhances HER2-specific B cell and T cell-mediated responses ex vivo in samples from patients treated with prior lines of HER2 antibody-based therapies. Stemming from these observations, a worthwhile future goal in the treatment of HER2+ breast cancer is to promote combinatorial approaches that better eradicate HER2+ cancer cells via enhanced immunological mechanisms., Competing Interests: Competing interests: AM reports grants from Roche and Eisai; personal fees from MacroGenics, Roche, Eisai, Novartis, and Lilly; participation in advisory boards from MacroGenics, Roche, Eisai, Novartis, Lilly. WJG has nothing to disclose. HSR reports personal fees for short-term consulting from Puma and Samsung; institutional grants for clinical research study activities from MacroGenics, Roche, Pfizer, Novartis, Lilly, Merck, Seattle Genetics, Odonate Therapeutics, Eisai, Sermonix, and Immunomedics, Daiichi Sankyo. MDP reports personal consulting fees from MacroGenics, AstraZeneca/Daiichi Sankyo, Pfizer, and Roche/Genentech, and grant support on this topic from the Parker Institute for Cancer Immunotherapy and the Mary Kay Foundation. JLN is an employee of MacroGenics. EPR was an employee of MacroGenics and is now an employee of Partner Therapeutics. FA was an employee of MacroGenics and is now an employee of AstraZeneca., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)