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1.
Sci Immunol ; 8(89): eadj5097, 2023 11 17.
Article in English | MEDLINE | ID: mdl-37976347

ABSTRACT

Myeloid cells facilitate T cell immune evasion in cancer yet are pliable and have antitumor potential. Here, by cotargeting myeloid activation molecules, we leveraged the myeloid compartment as a therapeutic vulnerability in mouse models of pancreatic cancer. Myeloid cells in solid tumors expressed activation receptors including the pattern recognition receptor Dectin-1 and the TNF receptor superfamily member CD40. In mouse models of checkpoint inhibitor-resistant pancreatic cancer, coactivation of Dectin-1, via systemic ß-glucan therapy, and CD40, with agonist antibody treatment, eradicated established tumors and induced immunological memory. Antitumor activity was dependent on cDC1s and T cells but did not require classical T cell-mediated cytotoxicity or blockade of checkpoint molecules. Rather, targeting CD40 drove T cell-mediated IFN-γ signaling, which converged with Dectin-1 activation to program distinct macrophage subsets to facilitate tumor responses. Thus, productive cancer immune surveillance in pancreatic tumors resistant to checkpoint inhibition can be invoked by coactivation of complementary myeloid signaling pathways.


Subject(s)
Pancreatic Neoplasms , Mice , Animals , CD40 Antigens , Immunotherapy
2.
Nat Commun ; 14(1): 6330, 2023 10 10.
Article in English | MEDLINE | ID: mdl-37816712

ABSTRACT

Although macrophages contribute to cancer cell dissemination, immune evasion, and metastatic outgrowth, they have also been reported to coordinate tumor-specific immune responses. We therefore hypothesized that macrophage polarization could be modulated therapeutically to prevent metastasis. Here, we show that macrophages respond to ß-glucan (odetiglucan) treatment by inhibiting liver metastasis. ß-glucan activated liver-resident macrophages (Kupffer cells), suppressed cancer cell proliferation, and invoked productive T cell-mediated responses against liver metastasis in pancreatic cancer mouse models. Although excluded from metastatic lesions, Kupffer cells were critical for the anti-metastatic activity of ß-glucan, which also required T cells. Furthermore, ß-glucan drove T cell activation and macrophage re-polarization in liver metastases in mice and humans and sensitized metastatic lesions to anti-PD1 therapy. These findings demonstrate the significance of macrophage function in metastasis and identify Kupffer cells as a potential therapeutic target against pancreatic cancer metastasis to the liver.


Subject(s)
Carcinoma, Pancreatic Ductal , Liver Neoplasms , Pancreatic Neoplasms , beta-Glucans , Humans , Animals , Mice , Kupffer Cells/pathology , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/pathology , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Liver Neoplasms/drug therapy , Liver Neoplasms/prevention & control , Liver Neoplasms/pathology
3.
Front Immunol ; 11: 629722, 2020.
Article in English | MEDLINE | ID: mdl-33597954

ABSTRACT

Cancer immunotherapy has revolutionized the treatment landscape in medical oncology, but its efficacy has been variable across patients. Biomarkers to predict such differential response to immunotherapy include cytotoxic T lymphocyte infiltration, tumor mutational burden, and microsatellite instability. A growing number of studies also suggest that baseline tumor burden, or tumor size, predicts response to immunotherapy. In this review, we discuss the changes in immune profile and therapeutic responses that occur with increasing tumor size. We also overview therapeutic approaches to reduce tumor burden and favorably modulate the immune microenvironment of larger tumors.


Subject(s)
Immunotherapy , Neoplasms , Tumor Burden/immunology , Humans , Neoplasms/immunology , Neoplasms/pathology , Neoplasms/therapy
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