Panni et al. developed ADH-503, a small-molecule agonist that partially activates CD11b, to target myeloid cells. In murine pancreatic ductal adenocarcinoma (PDAC) tumors, ADH-503 reduced the infiltration of CD11b+ myeloid cells, repolarized TAMs toward a proinflammatory phenotype, reduced Tregs, increased the frequency, proliferation, and activation of CD8+ and CD4+ T cells, and increased cross-presenting CD103+ cDC1s. ADH-503 improved tumor control and survival, enhanced chemotherapy- and radiation-induced antitumor effects, and rendered PDAC tumors responsive to anti-PD-1 and agonist 4-1BB.
Although checkpoint immunotherapies have revolutionized the treatment of cancer, not all tumor types have seen substantial benefit. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy in which very limited responses to immunotherapy have been observed. Extensive immunosuppressive myeloid cell infiltration in PDAC tissues has been postulated as a major mechanism of resistance to immunotherapy. Strategies concomitantly targeting monocyte or granulocyte trafficking or macrophage survival, in combination with checkpoint immunotherapies, have shown promise in preclinical studies, and these studies have transitioned into ongoing clinical trials for the treatment of pancreatic and other cancer types. However, compensatory actions by untargeted monocytes, granulocytes, and/or tissue resident macrophages may limit the therapeutic efficacy of such strategies. CD11b/CD18 is an integrin molecule that is highly expressed on the cell surface of these myeloid cell subsets and plays an important role in their trafficking and cellular functions in inflamed tissues. Here, we demonstrate that the partial activation of CD11b by a small-molecule agonist (ADH-503) leads to the repolarization of tumor-associated macrophages, reduction in the number of tumor-infiltrating immunosuppressive myeloid cells, and enhanced dendritic cell responses. These actions, in turn, improve antitumor T cell immunity and render checkpoint inhibitors effective in previously unresponsive PDAC models. These data demonstrate that molecular agonism of CD11b reprograms immunosuppressive myeloid cell responses and potentially bypasses the limitations of current clinical strategies to overcome resistance to immunotherapy.
Author Info: (1) Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA. (2) Department of Medicine, Washington University School of Medicine, St. Louis, MO 6
Author Info: (1) Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA. (2) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (3) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (4) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (5) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (6) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (7) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (8) Drug Discovery Center, Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612, USA. (9) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. (10) Drug Discovery Center, Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612, USA. (11) Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA. Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA. (12) Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA. Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA. (13) Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA. (14) Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA. (15) Drug Discovery Center, Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612, USA. (16) Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. ddenardo@wustl.edu. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
