A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade
Cell. 2018;175(4):984-997.e24. DOI 10.1016/j.cell.2018.09.006. PMCID PMC6410377.
How to cite
AMA
Jerby-Arnon L, Shah P, Cuoco MS, Rodman C, Su MJ, Melms JC, et al. A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade. Cell. 2018;175(4):984-997.e24. doi:10.1016/j.cell.2018.09.006APA
Jerby-Arnon, L., Shah, P., Cuoco, M. S., Rodman, C., Su, M.-J., Melms, J. C., et al. (2018). A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade. Cell, 175(4), 984-997.e24. https://doi.org/10.1016/j.cell.2018.09.006BibTeX
@article{jerbyarnon2018cancer,
title = {A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade},
author = {Jerby-Arnon, L. and Shah, P. and Cuoco, M. S. and Rodman, C. and Su, M.-J. and Melms, J. C. and others},
journal = {Cell},
volume = {175},
number = {4},
pages = {984-997.e24},
year = {2018},
doi = {10.1016/j.cell.2018.09.006}
}Checkpoint inhibitors clear some melanomas and do nothing for many others, and the reasons have been hard to read from the tumor itself. Much of the attention has gone to the immune cells, but the question here is what the cancer cells are doing to keep T cells out.
The authors sequenced RNA from single cells across 33 melanoma tumors and found a program switched on inside the malignant cells that tracks with T cells being excluded. Measured before treatment, the same program predicted who responded to anti-PD-1 therapy in a separate group of patients, and blocking CDK4/6 repressed the program and helped mouse tumors respond to immunotherapy. To check the pattern held in intact tissue, they stained 19 tumors for 14 proteins and imaged them on a RareCyte CyteFinder scanner.
Key findings
- Single-cell RNA sequencing of 33 melanoma tumors defined a resistance program in the cancer cells themselves. Measured before treatment, the program predicted response to anti-PD-1 therapy in an independent cohort of 112 patients.
- CDK4/6 inhibition repressed the program and shifted cells toward a less resistant state. Profiling two RB-sufficient melanoma lines before and after abemaciclib saw the strongly immune-resistant fraction fall from 10% to 2% and 0.6%, and CDK4/6 inhibition sensitized mouse tumors to immunotherapy.
- 14-plex tissue imaging on a CyteFinder scanner confirmed the program inside intact tumors. Cyclic immunofluorescence of 19 tumors for 14 proteins matched the in-situ resistance scores to the single-cell scores (R = 0.57), with malignant cells in T-cell-cold niches showing the predicted low HLA-A and high p53.
CyteFinder in the methods
“Stained slides from each round of CycIF were imaged with a CyteFinder slide scanning fluorescence microscope (RareCyte Seattle WA) using either a 10X (NA = 0.3) or 40X long- working distance objective (NA = 0.6). Imager5 software (RareCyte) was used to sequentially scan the region of interest in 4 fluorescence channels.”
— Jerby-Arnon et al., Cell (2018), Methods, “In situ imaging”
Why it matters for CyteFinder users
If your discovery comes from sequencing and you need to see it in tissue, this study shows the part a RareCyte CyteFinder scanner can play. The finding at the center of the paper, a resistance program inside malignant melanoma cells, came from single-cell RNA sequencing. That readout tells you which cells carry the program, but not where they sit or whether the pattern survives in intact tumor. To close that gap the authors went back to tissue: they stained 19 tumors for 14 proteins by cyclic immunofluorescence and captured every round on a CyteFinder slide-scanning fluorescence microscope, four channels at a time, at 10X or 40X. Because the method is cyclic, the same slide is stained and imaged across several rounds to build the 14-marker picture, and the CyteFinder is the scanner that records each round and registers them into one image. The pattern is worth borrowing. When a single-cell result needs confirming at the protein and spatial level, a whole-slide fluorescence scanner is what carries a marker-defined question back into tissue, so you can show where the signal actually sits.
