| First Author | Patel A | Year | 2021 |
| Journal | J Immunol | Volume | 207 |
| Issue | 5 | Pages | 1298-1309 |
| PubMed ID | 34362833 | Mgi Jnum | J:331194 |
| Mgi Id | MGI:6845022 | Doi | 10.4049/jimmunol.2100281 |
| Citation | Patel A, et al. (2021) Multimodal Intralesional Therapy for Reshaping the Myeloid Compartment of Tumors Resistant to Anti-PD-L1 Therapy via IRF8 Expression. J Immunol 207(5):1298-1309 |
| abstractText | 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-6C(lo)Ly-6G(+) polymorphonuclear (PMN)-MDSCs and CD11b(+)Ly-6C(hi)Ly-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. |
