期刊
CANCER IMMUNOLOGY RESEARCH
卷 9, 期 5, 页码 554-567出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-20-0905
关键词
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资金
- NIH [P50 CA168536, R21 CA198550, K99 CA226679]
- U.S. Department of Defense [W81XWH1810268]
- Live Like Bella Grant from the State of Florida [9LA03]
- NCI through a Cancer Center Support Grant [P30-CA076292]
- NIH/NCI [2T32CA009666-21]
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- NCI [CA16672]
- DPR Construction
- Moffitt Melanoma
- Skin Cancer Center of Excellence
- U.S. Department of Defense (DOD) [W81XWH1810268] Funding Source: U.S. Department of Defense (DOD)
In mouse models of BRAF- and NRAS-mutant melanoma, upfront immunotherapy enhances responses to targeted therapy. The sequence of IT -> TT modulates the immune environment, increasing infiltration of T cells and decreasing tumor-associated macrophages, leading to improved therapeutic outcomes. Durable responses to the IT -> TT sequence depend on T-cell activity and enrichment of a population of melanoma cells with increased expression of MHC class I and melanoma antigens.
Immunotherapy (IT) and targeted therapy (TT) are both effective against melanoma, but their combination is frequently toxic. Here, we investigated whether the sequence of IT (anti-PD-1)-> TT (ceritinib-trametinib or dabrafenib-trametinib) was associated with improved antitumor responses in mouse models of BRAF- and NRAS-mutant melanoma. Mice with NRAS-mutant (SW1) or BRAF-mutant (SM1) mouse melanomas were treated with either IT, TT, or the sequence of IT -> TT. Tumor volumes were measured, and samples from the NRAS-mutant melanomas were collected for immune-cell analysis, single-cell RNA sequencing (scRNA-seq), and reverse phase protein analysis (RPPA). scRNA-seq demonstrated that the IT -> TT sequence modulated the immune environment, leading to increased infiltration of T cells, monocytes, dendritic cells and natural killer cells, and decreased numbers of tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells. Durable responses to the IT -> TT sequence were dependent on T-cell activity, with depletion of CD8(+), but not CD4(+), T cells abrogating the therapeutic response. An analysis of transcriptional heterogeneity in the melanoma compartment showed the sequence of IT -> TT enriched for a population of melanoma cells with increased expression of MHC class I and melanoma antigens. RPPA analysis demonstrated that the sustained immune response induced by IT -> TT suppressed tumorintrinsic signaling pathways required for therapeutic escape. These studies establish that upfront IT improves the responses to TT in BRAF- and NRAS-mutant melanoma models.
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