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Multimodal Intralesional Therapy for Reshaping the Myeloid Compartment of Tumors Resistant to Anti-PD-L1 Therapy via IRF8 Expression.
Patel, Ankit; Oba, Takaaki; Kajihara, Ryutaro; Yokoi, Toshihiro; Abrams, Scott I; Ito, Fumito.
Afiliação
  • Patel A; Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY.
  • Oba T; Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY.
  • Kajihara R; Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY.
  • Yokoi T; Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY.
  • Abrams SI; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY; and.
  • Ito F; Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY; fumito.ito@roswellpark.org.
J Immunol ; 207(5): 1298-1309, 2021 09 01.
Article em En | MEDLINE | ID: mdl-34362833
Intralesional therapy is a promising approach for remodeling the immunosuppressive tumor microenvironment while minimizing systemic toxicities. A combinatorial in situ immunomodulation (ISIM) regimen with intratumoral administration of Fms-like tyrosine kinase 3 ligand (Flt3L), local irradiation, and TLR3/CD40 stimulation induces and activates conventional type 1 dendritic cells in the tumor microenvironment and elicits de novo adaptive T cell immunity in poorly T cell-inflamed tumors. However, the impact of ISIM on myeloid-derived suppressor cells (MDSCs), which may promote treatment resistance, remains unknown. In this study, we examined changes in the frequencies and heterogeneity of CD11b+Ly-6CloLy-6G+ polymorphonuclear (PMN)-MDSCs and CD11b+Ly-6ChiLy-6G- monocytic (M)-MDSCs in ISIM-treated tumors using mouse models of triple-negative breast cancer. We found that ISIM treatment decreased intratumoral PMN-MDSCs, but not M-MDSCs. Although the frequency of M-MDSCs remained unchanged, ISIM caused a substantial reduction of CX3CR1+ M-MDSCs that express F4/80. Importantly, these ISIM-induced changes in tumor-residing MDSCs were not observed in Batf3-/- mice. ISIM upregulated PD-L1 expression in both M-MDSCs and PMN-MDSCs and synergized with anti-PD-L1 therapy. Furthermore, ISIM increased the expression of IFN regulatory factor 8 (IRF8) in myeloid cells, a known negative regulator of MDSCs, indicating a potential mechanism by which ISIM decreases PMN-MDSC levels. Accordingly, ISIM-mediated reduction of PMN-MDSCs was not observed in mice with conditional deletion of IRF8 in myeloid cells. Altogether, these findings suggest that ISIM holds promise as a multimodal intralesional therapy to alter both lymphoid and myeloid compartments of highly aggressive poorly T cell-inflamed, myeloid-enriched tumors resistant to anti-PD-L1 therapy.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células Dendríticas / Linfócitos T / Neoplasias Mamárias Animais / Fatores Reguladores de Interferon / Células Supressoras Mieloides / Imunoterapia / Proteínas de Membrana Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: J Immunol Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células Dendríticas / Linfócitos T / Neoplasias Mamárias Animais / Fatores Reguladores de Interferon / Células Supressoras Mieloides / Imunoterapia / Proteínas de Membrana Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: J Immunol Ano de publicação: 2021 Tipo de documento: Article