A membrane-associated inhibitory axis of MHC-I presentation for cancer immune evasion
Bibliographic record
Abstract
Abstract Although the success of immune-checkpoint blockade has revolutionized cancer treatment, a number of tumors do not respond or develop resistance, including acute myeloid leukemia (AML). A potential mode of resistance is immune evasion of T-cell immunity involving aberrant MHC-I antigen presentation (AP). To map such mechanisms of resistance we identified key AP regulators using specific peptide-MHC-I-guided CRISPR/Cas9 screens in AML. The top-ranked negative regulators were surface protein Sushi Domain Containing 6 (SUSD6), Transmembrane Protein 127 (TMEM127), and the E3 ubiquitin ligase WWP2. SUSD6 is abundantly-expressed in AML and multiple solid cancers, ablation of which profoundly enhanced AP and reduced tumor growth in CD8+ T cell-dependent manner. Mechanistically, SUSD6 forms a molecular complex with TMEM127 and MHC-I, recruiting WWP2 for MHC-I lysosomal degradation. Together with the SUSD6-TMEM127-WWP2 gene signature negatively-correlated with cancer survival, our findings define a membrane-associated AP inhibitory axis as broadly-applicable therapeutic targets for both leukemia and solid cancers. This work is supported by the Mark Foundation ASPIRE Award to J.W. I.A. is supported by the NIH (NCI and NHLBI) (R01CA216421, R01 CA173636, 1R01CA228135, R01CA242020, 1R01HL159175), the Vogelstein Foundation and the Evans MDS Foundation. J.W. is supported by the NIH (R37CA273333-01, R21AI163924-02). Q.L. is supported by the Cancer Research Institute Irvington Postdoctoral Fellowship.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".