Chromatin Accessibility as a Predictor of Response to Immune Checkpoint Blockade
DOI:
https://doi.org/10.5281/zenodo.22760424Keywords:
ATAC-seq, immune checkpoint blockade, T cell exhaustion, chromatin accessibility, PD-1, tumor-infiltrating lymphocytes, biomarkerAbstract
Response to immune checkpoint blockade varies substantially across patients with solid tumors, and while
pre-treatment tumor mutational burden and PD-L1 expression provide partial predictive value, a large fraction of
response variability remains unexplained, motivating interest in chromatin-based biomarkers that might capture the
functional state of tumor-infiltrating T cells more directly than mutation- or protein-based measures alone. Here we
profiled chromatin accessibility by ATAC-seq in CD8+ tumor-infiltrating lymphocytes sorted from pre-treatment
biopsies of 94 patients with advanced melanoma or non-small-cell lung cancer initiating anti-PD-1 monotherapy,
and related accessibility patterns to subsequent radiographic response. A chromatin accessibility signature at 312
genomic regions, derived from a discovery cohort of 61 patients and validated in an independent cohort of 33
patients, distinguished responders from non-responders with an area under the receiver operating characteristic
curve of 0.81 in the validation cohort, outperforming a tumor-mutational-burden-based classifier (area under the
curve 0.64) and a PD-L1-immunohistochemistry-based classifier (area under the curve 0.59) assessed in the same
patients. Regions comprising the predictive signature were disproportionately located at loci encoding effector and
memory-precursor T cell programs rather than terminal exhaustion programs, and responders showed significantly
greater baseline accessibility at these loci relative to non-responders, consistent with a less terminally exhausted
pre-treatment chromatin state predicting subsequent response. Combining the chromatin accessibility signature
with tumor mutational burden in a joint classifier modestly improved discrimination over the chromatin signature
alone (area under the curve 0.85), indicating partially non-redundant predictive information. These results identify a
pre-treatment chromatin accessibility signature in tumor-infiltrating CD8+ T cells that outperforms established
genomic and protein biomarkers for predicting response to anti-PD-1 checkpoint blockade.
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