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Preprint WatchModerateAugust 2nd, 2026

EZH1/2 inhibition improves immunotherapy response through MHC Class II de-repression and neutrophil reprogramming

Childress, A. R.; Esoe, D.-P. I.; Song, X.; Gosser, C. M.; Lin, Y.; Plaugher, D. R.; DuCote, T. J.; Naughton, K. J.; Skaggs, E. M.; Yang, H.; Goettl, R.; Liu, J.; Hao, Z.; Fliss, A. E.; Honma, D.; Burus, T.; Lei, F.; Huang, B.; Beswick, E.; Brainson, C. F.

EZH1/2 inhibition with valemetostat augments anti-PD-1 antitumor response by de-repressing tumor cell MHC Class II and reprogramming systemic neutrophil maturation.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint reports that the EZH1/2 inhibitor valemetostat augmented anti-PD-1 responses in lung squamous cell carcinoma models, with de-repression of tumor cell MHC Class II and systemic neutrophil maturation offered as the mechanism. The claim is preclinical and the effect is a combination effect, so it does not conflict with any clinical result on its own. It does land on a target the Claidex graph flagged today. The camrelizumab plus apatinib post-mortem (camrelizumab-apatinib-pdcd1-first-line-cervical-cancer-phase2-efficacy-failure) records a randomized first-line trial that stopped after 35 patients with no superior progression-free survival, and PDCD1 carries a mechanism risk score of 40 driven almost entirely by saturation, with 26 clinical-stage PD-1 agents already in development. The pattern worth watching is that PD-1 combination hypotheses continue to be generated faster than they can be tested, and that the failure mode in the clinical record was trial size rather than mechanism. Any program translating this MHC Class II and neutrophil hypothesis should pre-specify the effect size it expects from the combination and size the first randomized comparison to detect it. Note that this record is version 3 of a preprint first posted on 1 June 2026 and appearing in the bioRxiv feed for 1 August 2026.

Abstract excerpt

Squamous cell carcinoma of the lung is a difficult-to-treat cancer with high prevalence in the US, and particularly in Kentucky. Here, we sought to test if the EZH1/2 inhibitor valemetostat improves anti-PD1 responses in squamous cell lung cancer models, and to develop ex vivo models to test immunotherapy drug combinations. We found that valemetostat augmented anti-tumor responses to anti-PD1 therapy, led to up-regulation of tumor cell specific Major Histocompatibility Complex Class II (MHC Class II), and drove systemic neutrophil maturation. Likewise, Ezh2 knock-out mice produced neutrophils that were more apoptotic, less migratory, and less able to produce extracellular nets, but had similar ability to kill bacteria as Ezh2-WT neutrophils. To test tumor responses to differing neutrophil populations, we engineered three-dimensional air-liquid interface cultures with tumoroids, lung mesenchymal cells, and T cells, with and without bone marrow containing neutrophils and myeloid progenitors from distinct donors. Bone marrow from tumor-naive or mice with actively growing untreated tumors boosted tumoroid growth, while bone marrow from spontaneously tumor-rejected or mice with tumors treated with valemetostat was anti-tumor. MHC Class II blockade lowered the ability of bone marrow to boost tumor growth, and reduced the ability of valemetostat with anti-PD1 to reduce tumoroid growth. Patient samples revealed a strong negative correlation between EZH2 and MHC Class II, suggesting that targeting EZH2 activity could lead to marked increase in MHC Class II and improve treatment responses in lung squamous cell carcinomas.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.