humanJAK1/JAK2 loss-of-function drives both primary and acquired anti-PD-1 resistance. Zaretsky 2016 (NEJM) documented acquired JAK1 or JAK2 LOF (with LOH) plus one B2M truncating mutation in 3 of 4 melanoma patients relapsing on pembrolizumab1. Shin 2017 extended the same mechanism to primary non-responders despite high TMB2. Rare (<5% of all failures) but biochemically definitive; the mutant tumors are non-responsive to IFN-γ.
mousePTPN2 is the tumor-intrinsic inverse of JAK/STAT resistance. An in vivo CRISPR screen (Manguso 2017) identified Ptpn2 loss in tumor cells as an ICI sensitizer by amplifying IFN-γ/JAK-STAT signaling3. Now clinically pursued (e.g., ABBV-514 class).
humanHLA-I allele-specific LOH is a common, positively selected immune-escape event. McGranahan 2017 (TRACERx 100) used LOHHLA to show HLA LOH in ~40% of NSCLCs, enriched at metastatic sites, with subclonal neoantigen association4. Replicated pan-cancer.
humandMMR/MSI-H tumors respond broadly to pembrolizumab (Le 2017)5; basis of the first tissue-agnostic FDA approval and of KEYNOTE-177 for 1L dMMR mCRC6. The presumed mechanism is massive neoantigen load from mismatch-repair failure.
humanHLA-I LOH is not deterministic. Landmark biology established the mechanism; clinical implementation has been more nuanced. Some HLA-LOH patients still respond to anti-PD-1, especially when residual heterozygous HLA alleles present the dominant neoantigen(s). The predictive signal depends on which allele is lost, the tumor type, and the neoantigen landscape. So the correct clinical reading is "HLA LOH is a risk marker, not a disqualifier."
humanβ2M loss sometimes doesn't prevent response. The canonical acquired-resistance mechanism in Zaretsky 2016 documents B2M loss causing PD-1 resistance, but rare B2M-low/null tumors still respond — likely via NK-mediated killing or non-classical HLA presentation. β2M/JAK lesions together explain only a minority of acquired failures in larger cohorts.
humanTMB does not generalize cleanly across tumor types. Rizvi 2015 established the NSCLC association7; Snyder 2014 the melanoma anti-CTLA-4 association8. FDA's pan-tumor pembrolizumab approval for TMB ≥10 mut/Mb has been controversial — certain high-TMB histologies (some gliomas) show limited benefit. The threshold is assay- and context-dependent.
humanThe "shared neoantigen tetrapeptide signature" from Snyder 2014 did not replicate. Only the coarse TMB association survived.
humanKEYNOTE-177 showed dMMR is not universal within mCRC. ~29% of patients had primary progression on pembrolizumab (worse than chemo in the first 6 months), and final OS did not reach statistical significance (HR ~0.74, crossover confounded)6. dMMR is necessary-but-not-sufficient even in its strongest indication.
mousePAR-2 (F2RL1) activation suppresses DC antigen presentation in lung cancer. A selective negative allosteric modulator (I-117) restores presentation and synergizes with anti-PD-1 in preclinical models — novel GPCR-to-APC axis with a druggable lead (this period's literature).
humanTumor B2M expression as a TMB/PD-L1-independent response biomarker in R/M HNSCC progressing on anti-PD-1 (multi-omics 2026). Moves B2M from "LOF = resistance" framing toward a graded expression biomarker.
HLA LOH detection (LOHHLA, companion tools) is not yet a clinical-grade decision aid; report it as risk context, not a disqualification.
dMMR / MSI-H remains the strongest single biomarker, but KEYNOTE-177's biphasic PFS warns that a subset will fail immediately; early radiologic reassessment at ~2 months is worth considering.
TMB thresholds vary by assay and histology; treat the FDA pan-tumor cutoff as a heuristic, not a universal predictor.