Research ArticleCancer

Agonism of CD11b reprograms innate immunity to sensitize pancreatic cancer to immunotherapies

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Science Translational Medicine  03 Jul 2019:
Vol. 11, Issue 499, eaau9240
DOI: 10.1126/scitranslmed.aau9240

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Manipulating myeloid cells through CD11b

Attempts to alter the phenotype or remove suppressive myeloid cells from the tumor microenvironment are working their way to the clinic. Panni et al. tested a small-molecule agonist of the integrin CD11b to mitigate myeloid cell immunosuppression in mouse models of pancreatic ductal adenocarcinoma. This drug, ADH-503, reduced myeloid cell recruitment and altered the phenotypes of myeloid cells within the tumor. ADH-503 treatment increased responses to chemotherapy or radiation and also rendered normally resistant tumors sensitive to checkpoint blockade, as T cell phenotypes and recruitment were also modified indirectly. These exciting results show how targeting an integrin on myeloid cells could improve treatment for a devastating cancer type.

Abstract

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.

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