Abstract 5636: Restoration of tumor immunosurveillance in tasmanian devil facial tumor disease
Bibliographic record
Abstract
Abstract Transmissible cancer is a rare, but mechanistically not understood form of cancer that can directly spread between individuals. At least six species in the animal kingdom harbor clonal cancers that spread horizontally. These diseases include the fatal devil facial tumor disease (DFTD) in Tasmanian devils, a sexually transmitted sarcoma in dogs, and leukemia-like cancers in mollusks. DFTD is an allogeneic graft of Schwann cell origin, which is transmitted by direct transfer of cancer cells from one individual to another as a result of biting behavior. Two strains of DFTD, DFT1 and DFT2, emerged independently in the population of Tasmanian devils. It is essential to gain mechanistic understanding of horizontal cancers to understand how cancer cells escape host immune cells. We designed an integrative systems biology approach using primary biopsies, established Tasmanian devil tumor and control cell lines and mouse xenograft model. Specifically, we combined pharmacological drug screening, transcriptomics, epigenetics, proteomics and comparative pathology to unveil aberrant signaling pathways in DFTD. We found that DFT1 tumor cells express high levels of phosphorylated ERBB2 and ERBB3 tyrosine kinase receptor and they are exquisitely vulnerable to ERBB kinase inhibitors. Blockade of the hyperactive ERBB-STAT3 axis with ERBB inhibitor sapitinib or with the STAT3 inhibitor DR-1-55 led to recovery of MHC-I expression, suggesting that immune escape could be antagonized by blockade of hyperactive ERBB-STAT3 action. In contrary to DFT1, progression of DFT2 is known to be associated with PDGF receptor amplification. This proposed an attractive pharmacological approach of targeted inhibition of PDGFR by broad kinase inhibitor imatinib. We validated in xenograft mouse model that targeted inhibition of PDGFR results in the efficient reduction of tumor growth as well as restoration of MHC-I gene expression. In summary, we identified a critical role for hyperactive tyrosine kinase-STAT signaling whose pharmacological inhibition resulted in arrested growth and possible restoration of immune cell recognition. We validated that DFT2 displays a distinct oncogene mechanism than DFT1, but pharmacologic inhibition of hyperactive driver kinase pathway leads to similar restoration of MHC-I expression. This link between the hyperactive pathway and MHC-I-mediated tumor immunosurveillance in both DFTD strains provides mechanistic insights into horizontal transmissibility and suggests a strategy to save Tasmanian devils from extinction. Citation Format: Anna Orlova, Lindsay Kosack, Alexandra M. Popa, Csilla Viczenczova, Alexander Lercher, Elvin D. de Araujo, Patrick Gunning, Richard Moriggl, Andreas Bergthaler. Restoration of tumor immunosurveillance in tasmanian devil facial tumor disease [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5636.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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) | 0.001 | 0.000 |
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 teacher head, 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".