Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2020 GM-CSF-based treatments in COVID-19: reconciling opposing therapeutic approaches Lang, Frederick M ; Lee, Kevin M-C ; Teijaro, John R ; Becher, Burkhard ; Hamilton, John A Abstract: Therapeutics against coronavirus disease 2019 (COVID-19) are urgently needed. Granulocyte- macrophage colony-stimulating factor (GM-CSF), a myelopoietic growth factor and pro-inflammatory cytokine, plays a critical role in alveolar macrophage homeostasis, lung inflammation and immunological disease. Both administration and inhibition of GM-CSF are currently being therapeutically tested in COVID-19 clinical trials. This Perspective discusses the pleiotropic biology of GM-CSF and the scientific merits behind these contrasting approaches. DOI: https://doi.org/10.1038/s41577-020-0357-7 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-194043 Journal Article Published Version The following work is licensed under a Creative Commons: Attribution 4.0 International (CC BY 4.0) License. Originally published at: Lang, Frederick M; Lee, Kevin M-C; Teijaro, John R; Becher, Burkhard; Hamilton, John A (2020). GM-CSF-based treatments in COVID-19: reconciling opposing therapeutic approaches. Nature Reviews. Immunology, 20(8):507-514. DOI: https://doi.org/10.1038/s41577-020-0357-7 PERSPECTIVES mutations that ablate GM-CSFR function) causes pulmonary alveolar proteinosis GM-CSF-based treatments in (PAP), a life-threatening interstitial lung disease in which dysfunctional alveolar COVID-19: reconciling opposing macrophages cannot clear surfactant16. Patients with PAP have increased therapeutic approaches susceptibility to opportunistic infections due to defective antimicrobial function Frederick M. Lang , Kevin M.-C. Lee , John R. Teijaro, Burkhard Becher of alveolar macrophages and basal circulating neutrophils, caused by impaired and John A. Hamilton GM-CSF signalling16,17. In mice, GM-CSF Abstract | Therapeutics against coronavirus disease 2019 (COVID-19) are urgently has been reported to be required for the needed. Granulocyte–macrophage colony-stimulating factor (GM-CSF), a steady-state maintenance of non-lymphoid tissue-resident CD103+ dendritic cells across myelopoietic growth factor and pro-inflammatory cytokine, plays a critical role in multiple tissues, and this population of cells alveolar macrophage homeostasis, lung inflammation and immunological disease. was shown to be critically important for Both administration and inhibition of GM-CSF are currently being therapeutically the initiation of CD8+ T cell responses in the tested in COVID-19 clinical trials. This Perspective discusses the pleiotropic lung18,19. GM-CSF thus serves a crucial role biology of GM-CSF and the scientific merits behind these contrasting approaches. in normal lung health and can be important for host defence. Coronavirus disease 2019 (COVID-19), This Perspective provides a brief overview Role in inflammation. During inflammation, caused by severe acute respiratory syndrome of the pleiotropic biology of GM-CSF and GM-CSF can be secreted by several coronavirus 2 (SARS-CoV-2), has turned examines the preclinical and clinical studies different cell types, including epithelial into a global pandemic. No agent has supporting the use of both sargramostim cells and leukocytes, and is a critically proved effective against coronavirus and GM-CSF-targeting mAbs in COVID-19. important cytokine that can drive both infections, and the development of novel innate and adaptive immune responses therapeutics is critical to solve this public GM-CSF overview (fig. 1). GM-CSFR is mainly expressed health crisis. Granulocyte–macrophage Role in homeostasis. Macrophage on myeloid cells, generally restricting the colony-stimulating factor (GM-CSF), an colony-stimulating factor (M-CSF), direct-acting function of GM-CSF to cells important myelopoietic growth factor and granulocyte colony-stimulating factor of this lineage. GM-CSF broadly serves pro-inflammatory cytokine, has attracted (G-CSF) and GM-CSF are implicated in two important roles during the immune great interest as a therapeutic target in myelopoiesis, the production of monocytes, response: it polarizes mature myeloid COVID-19. Increased percentages of macrophages, dendritic cells and cells into a pro-inflammatory phenotype GM-CSF-expressing leukocytes have granulocytes (neutrophils, eosinophils (paracrine/autocrine function), and it been found in the blood of patients with and basophils) from progenitor cells. governs ‘emergency myelopoiesis’, expanding COVID-19 (REF.1), and inhibition of GM-CSF M-CSF and G-CSF appear to be involved and mobilizing progenitor myeloid cells to has shown benefit in animal studies of in steady-state myelopoiesis, given that null sites of inflammation (endocrine function)2. many hyperinflammatory conditions2,3 mutants of the encoding genes in mice cause GM-CSF-activated myeloid cells can secrete that are thought to be pathologically severe phenotypes (for example, skeletal reactive oxygen species and express elevated similar to late stages of COVID-19. As of and sensory defects and neutropenia)10–12. levels of pro-inflammatory cytokines 28 May 2020, six companies had initiated By contrast, GM-CSF is barely detectable (such as IL-1, IL-6 and tumour necrosis randomized controlled clinical trials and in the blood of healthy individuals and is factor (TNF)) and a variety of chemokines open-label studies and/or expanded access/ thought to serve less of a role in homeostatic (such as CCL2, IL-8 and CCL17, which compassionate use programmes assessing myelopoiesis, as evidenced by the fact that can attract monocytes, neutrophils and the use of monoclonal antibodies (mAbs) to GM-CSF-deficient mice have a virtually lymphocytes, respectively)2. GM-CSF can GM-CSF or GM-CSF receptor (GM-CSFR) normal lifespan and have less dramatic also enhance the ability of dendritic cells to treat various stages of COVID-19 alterations in the basal myeloid system13,14. to prime T cells during antigen-specific (REFS4–9). Conversely, GM-CSF plays an Importantly, however, GM-CSF is immune responses14,18. A distinct subset of + important role in alveolar macrophage known to be a critical homeostatic factor CD4 T helper cells (TH cells) that produce homeostasis and lung pathogen clearance2, in lung alveoli, where it is produced at low primarily GM-CSF has been identified20–23. and investigator-initiated trials are studying levels for the development and long-term These T cells can heighten the immune the administration of recombinant human maintenance of alveolar macrophages15,16. response by activating pro-inflammatory GM-CSF (sargramostim) in patients with Severe deficiency of GM-CSF (for example, myeloid cells and recruiting them to respiratory failure due to COVID-19. due to autoantibodies to GM-CSF or sites of inflammation20–22. Thus, it has NATURE REVIEWS | IMMUNOLOGY VOLUME 20 | AUGUST 2020 | 507 PERSPECTIVES Inflamed tissue Antigen Circulation Bone marrow (e.g. lungs) (e.g. SARS-CoV-2) GM-CSF GM-CSF Host cell Activation Recruitment to tissue GM-CSF Activated lymphocytes Mobilization Expansion • Survival • Proliferation • Differentiation Activation IL-1, IL-6, TNF, IL-1, IL-6, TNF, • Survival CCL2, IL-8, CCL2, IL-8, CCL17 CCL17 • Proliferation Mature • Differentiation myeloid cells Pro-inflammatory cytokines and chemokines Non-activated Activated Pro-inflammatory lymphocytes lymphocytes Immature Progenitor Dendritic myeloid cells cells cell Immune activating Lymph node Fig. 1 | GM-CSF and inflammation. The immune response, including gran- thereby aiding in the recruitment and activation of new myeloid cells. ulocyte–macrophage colony-stimulating factor (GM-CSF) upregulation, GM-CSF levels can also be elevated systemically to induce ‘emergency can be triggered when an antigen induces a ‘danger’ signal from a host cell. myelopoiesis’, expanding and mobilizing immature myeloid/progenitor During this response, GM-CSF can act locally in inflamed tissue to induce haematopoietic cells in the circulation and bone marrow. These the survival, proliferation and/or differentiation of myeloid cells, such as GM-CSF-dependent responses thus heighten the inflammatory response monocytes/macrophages and neutrophils. More specifically, GM-CSF in inflamed or diseased tissue. The broad range of immunological can potentially do the following: activate mature myeloid cells to a activities of GM-CSF can form part of positive-feedback loops/networks pro-inflammatory phenotype with enhanced cytokine (for example, IL-1, that can initiate and maintain disease-causing hyperactive or chronic IL-6 and tumour necrosis factor (TNF)) and chemokine (for example, CCL2, immune responses. GM-CSF has also been shown to enhance antimicrobial IL-8 and CCL17) secretory capacity; recruit immature myeloid cells from host defence and lung barrier repair (not shown). Blue arrows mean the circulation and aid in their terminal differentiation; and develop/stim- ‘secretes’, black arrows mean ‘acts on’, dotted arrows indicate movement ulate dendritic cells to prime the adaptive immune response. Activated or differentiation and ‘host cell’ refers to various haematopoietic and lymphocytes (for example, GM-CSF-producing T helper cells) can migrate non-hematopoietic cell types. SARS-CoV-2, severe acute respiratory into diseased tissue and the circulation, serving as a source of GM-CSF, syndrome coronavirus