Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity
| Autor: | Kathryn Miller-Jensen, Marcus Bosenberg, Alexandra Kuhlmann, Durga Thakral, Curtis J. Perry, Joel W Sher, Andrés R. Muñoz-Rojas, Susan M. Kaech, Laura N Kellman, Victor Y. Du, William Damsky, Robert A. Amezquita, J. Wang, Katrina Meeth |
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| Rok vydání: | 2018 |
| Předmět: |
Proto-Oncogene Proteins B-raf
0301 basic medicine Myeloid Transcription Genetic T-Lymphocytes T cell medicine.medical_treatment Immunology Melanoma Experimental Article Interferon-gamma Mice 03 medical and health sciences Immune system Cancer immunotherapy Neoplasms medicine Animals Immunology and Allergy Myeloid Cells RNA Messenger CD40 Antigens Research Articles Cell Proliferation Inflammation Tumor microenvironment Tumor Necrosis Factor-alpha business.industry Macrophages Melanoma PTEN Phosphohydrolase Immunotherapy medicine.disease Survival Analysis 3. Good health Phenotype 030104 developmental biology medicine.anatomical_structure Receptors Granulocyte-Macrophage Colony-Stimulating Factor Cancer research Tumor necrosis factor alpha business |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| DOI: | 10.1084/jem.20171435 |
| Popis: | Perry et al. show that myeloid-targeted immunotherapy with a combination of anti-CD40 and CSF-1R inhibition synergistically induces a proinflammatory microenvironment that suppresses CPI-resistant tumors in a TNF-α– and IFN-γ–dependent manner. Eliciting effective antitumor immune responses in patients who fail checkpoint inhibitor therapy is a critical challenge in cancer immunotherapy, and in such patients, tumor-associated myeloid cells and macrophages (TAMs) are promising therapeutic targets. We demonstrate in an autochthonous, poorly immunogenic mouse model of melanoma that combination therapy with an agonistic anti-CD40 mAb and CSF-1R inhibitor potently suppressed tumor growth. Microwell assays to measure multiplex protein secretion by single cells identified that untreated tumors have distinct TAM subpopulations secreting MMP9 or cosecreting CCL17/22, characteristic of an M2-like state. Combination therapy reduced the frequency of these subsets, while simultaneously inducing a separate polyfunctional inflammatory TAM subset cosecreting TNF-α, IL-6, and IL-12. Tumor suppression by this combined therapy was partially dependent on T cells, and on TNF-α and IFN-γ. Together, this study demonstrates the potential for targeting TAMs to convert a “cold” into an “inflamed” tumor microenvironment capable of eliciting protective T cell responses. |
| Databáze: | OpenAIRE |
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