Loss of tumor cell MHC Class II drives insensitivity of BRAF-mutant anaplastic thyroid cancers to MAPK inhibitors
Tiedje, V.; Greenberg, J.; Qin, T.; Im, S.-Y.; Krishnamoorthy, G. P.; Boucai, L.; Xu, B.; French, J. D.; Sherman, E. J.; Ho, A. L.; De Stanchina, E.; Socci, N. D.; Jin, J.; Ghossein, R.; Knauf, J. A.; Koche, R. P.; Fagin, J. A.
Show abstract
Cancer cells present neoantigens dominantly through MHC class I (MHCI) to drive tumor rejection through cytotoxic CD8+ T-cells. There is growing recognition that a subset of tumors express MHC class II (MHCII), causing recognition of antigens by TCRs of CD4+ T-cells that contribute to the anti-tumor response. We find that mouse BrafV600E-driven anaplastic thyroid cancers (ATC) respond markedly to the RAF + MEK inhibitors dabrafenib and trametinib (dab/tram) and that this is associated with upregulation of MhcII in cancer cells and increased CD4+ T-cell infiltration. A subset of recurrent tumors lose MhcII expression due to silencing of Ciita, the master transcriptional regulator of MhcII, despite preserved interferon gamma signal transduction, which can be rescued by EZH2 inhibition. Orthotopically-implanted Ciita-/- and H2-Ab1-/- ATC cells into immune competent mice become unresponsive to the MAPK inhibitors. Moreover, depletion of CD4+, but not CD8+ T-cells, also abrogates response to dab/tram. These findings implicate MHCII-driven CD4+ T cell activation as a key determinant of the response of Braf-mutant ATCs to MAPK inhibition.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- MEK1/2 inhibition transiently alters the tumor immune microenvironment to enhance immunotherapy efficacy against head and neck cancer 95%
- Spatial colocalization and combined survival benefit of natural killer and CD8 T cells despite profound MHC class I loss in non-small cell lung cancer 95%
- KLRG1 marks tumor-infiltrating CD4 T cell subsets associated with tumor progression and immunotherapy response 94%
Similar papers in this journal
- Immunosuppressive tumor microenvironment of osteosarcoma 93%
- Transcriptomic analyses of MYCN-regulated genes in anaplastic Wilms' tumour cell lines reveals oncogenic pathways and potential therapeutic vulnerabilities 93%
- Intertumoral Genetic Heterogeneity Generates Distinct Tumor Microenvironments in a Novel Murine Synchronous Melanoma Model 93%
Similar papers in this journal
- MAX inactivation deregulates the MYC network and induces neuroendocrine neoplasia in multiple tissues 96%
- TERT accelerates BRAF mutant-induced thyroid cancer dedifferentiation and progression by regulating ribosome biogenesis 96%
- Autocrine TGFβ2 enforces a transcriptionally hybrid cell state in Ewing sarcoma 94%
Similar papers in this journal
- Lymphatic-Preserving Treatment Sequencing with Immune Checkpoint Inhibition Unleashes cDC1-Dependent Antitumor Immunity in HNSCC 95%
- Multidimensional Characterization of Soft-Tissue Sarcomas with FUS-TFCP2 or EWSR1-TFCP2 Fusions 95%
- Anti-CSF-1R therapy with combined immuno- chemotherapy coordinate an adaptive immune response to eliminate macrophage enriched Triple Negative Breast Cancers 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.