Table 1.
Immune checkpoint inhibitor resistance landscape in melanoma
| PD1 PROG (n = 22) | Biopsy site | Resistance mechanisms in PD1 PROG melanoma cell lines | Tumor cells | Tumor microenvironment | |
|---|---|---|---|---|---|
| DNA | RNA/Protein | (Dissociate) | (Dissociate) | ||
| SCC16-0016 | Pancreas | JAK2 loss | De-differentiation | Low MHC-I/II | Low CD8, low CD8/Treg |
| SMU16-0150 | Scalp | PTEN loss | Intrinsic IFNγ, de-differentiation | High MHC-I, high PD-L1, low MHC-II | Low CD45+, high Mϕ, low CD8 T |
| SMU15-0404 | Axillary LN | Intrinsic IFNγ, de-differentiation | High MHC-I/II | Low activated CD8 T | |
| SCC15-0534 | Neck | Intrinsic IFNγ, de-differentiation | Low MHC-I/II, High PD-L2 | High Mϕ, high Tregs, low CD8/Treg | |
| SMU13-0183M3 | Brain | Intrinsic IFNγ, de-differentiation | High MHC-II | ||
| SMU13-0183M7 | Brain | Intrinsic IFNγ, de-differentiation | Low MHC-I, high MHC-II | Low CD45+ | |
| SMU14-0301 | Retroperitoneal LN | Intrinsic IFNγ, de-differentiation | NA | NA | |
| WMD-084#2 | Ovaries | De-differentiation | NA | NA | |
| WMD15-083#1 | Small bowel | De-differentiation | High PD-L2 | Low activated CD8 T | |
| WMD15-083#2 | Large colon | De-differentiation | Low MHC-I/II, high PD-L2 | Low CD45+, low CD8 T, low activated CD8 T | |
| SMU-059 | Flank SC | MHC-I, MHC-II LOH | De-differentiation | Low MHC-I/II, high PD-L2 | Low CD45+ |
| WMD17-0112 | Thigh SC | MHC-I, MHC-II LOH | Low MHC-I/II, high PD-L2 | High Tregs | |
| SCC13-0156 | Retroperitoneal LN | B2M loss | CIITA silencing (MHC-II low) | Low MHC-I/II | High Tregs, low CD8/Treg, high activated Tregs |
| SMU-092 | Breast |
B2M loss HLA-A germline homozygous |
CIITA silencing (MHC-II low) | Low MHC-I/II, high PD-L2 | Low activated CD8 T |
| SCC11-0270 | Brain | CIITA silencing (MHC-II low) | NA | NA | |
| SMU17-0263 | Brain | PTEN loss, HLA-A germline homozygous | CIITA silencing (MHC-II low) | Low MHC-I | High Mϕ, high activated Tregs |
| SMU11-0376M4 | Brain | PTEN loss, HLA-A germline homozygous | Low MHC-II | Low CD45+ | |
| SMU11-0376M2 | Brain | PTEN loss, HLA-A germline homozygous | High MHC-I, low MHC-II, high PD-L1 | Low CD45+ | |
| SCC15-0528 | Thigh SC | PTEN truncation, HLA-A germline homozygous | Low MHC-I/II, high PD-L1 | Low CD45+, high Mϕ, low CD8 T, low CD8/Treg | |
| WMD-084#1 | Ovaries | High PD-L1 | High Tregs, low CD8/Treg | ||
| SCC15-0111 | Brain | High MHC-II | |||
| SMU15-0229 | Brain | High MHC-I/II, high PD-L1 | High activated Tregs | ||
LOH loss of heterozygosity, LN lymph node, SC subcutaneous, NA data not available; differentiation status based on protein analysis of MITF, AXL, and NGFR.
Low MHC-I, MHC-I tumor/TILs <0.8 (median); high MHC-I, MHC-I tumor/TILs >1.5 (top quartile); Low MHC-II, MHC-II tumor/TILs <0.3 (median); high MHC-II, MHC-II tumor/TILs >1.5 (top quartile); High PD-L1, PD-L1 tumor/TILs >0.8 (top quartile); High PD-L2, PD-L2 tumor/TILs >1.8 (top quartile); Low CD8, <29% CD45+ (bottom quartile); Low CD8/Treg ratio, <2.9 (bottom quartile); Low activated CD8, PD1high Ki67+ CD8 subset <11% of CD45RO+CD8 T cells (bottom quartile); Low CD45+, <2.8% of total (bottom quartile); High macrophages (Mϕ), >22% of CD45+ fraction (top quartile); High Tregs, >8.1% of CD45+ (top quartile); High activated Tregs, PD1+Ki67+subset >36% of CD45RO+Tregs (top quartile).