Abstract 3981: The Shc1 scaffold protein simultaneously balances Stat1 and Stat3 activity in breast cancer to promote immune suppression and resistance to immunotherapy
Bibliographic record
Abstract
Abstract Receptor and cytoplasmic tyrosine kinases are key signal integrators in poor outcome breast cancers that are central to the establishment of an immunosuppressive microenvironment. Immunotherapies represent an emerging approach within the armament of anti-cancer agents. Although the efficacy of tyrosine kinase inhibitors relies, in part, on their ability to augment adaptive immunity, the increased heterogeneity and functional redundancy of the tyrosine kinome in poor outcome breast cancers represents a significant hurdle to achieving durable responses to immunotherapies. We previously identified the Shc1 (ShcA) scaffold protein, a central regulator of tyrosine kinase signaling, as essential for promoting immune suppression. We recently showed that the ShcA pathway simultaneously activates STAT3 immunosuppressive signals and impairs STAT1-driven immune surveillance in breast cancer cells. Impaired phosphorylation of select tyrosine residues on ShcA potently and selectively reduces STAT3 activation in breast tumors, profoundly sensitizing them to immune checkpoint inhibitors and tumor vaccines. Meanwhile, impaired phosphorylation of other select tyrosine residues on ShcA potently increased antigen presentation and sensitivity to tumor vaccines in preclinical mouse models. Based on these results, we have set out to elucidate protein interactors dependent on distinct ShcA phospho-tyrosines to regulate STAT1 and STAT3 signaling axis that aid tumor driven immune suppression. We combined affinity-purification mass spectrometry (AP/MS) and proximity-dependent biotin identification (BioID) followed by mass spectrometry (BioID/MS). Known interactors of ShcA as well novel interactors have been identified. Promising candidates that could be critical in immune suppression downstream of ShcA have been validated to be true interactors by co-IP and BioID assays. They have been screened for immune regulation in vitro for further modulation in vivo. Currently, inhibitors of phospho-tyrosine motifs of ShcA do not exists. Therefore, the development of pharmacological inhibitors to prevent phospho-tyrosine ShcA dependent STAT3 signaling or relieve suppression of STAT1 signaling may be an attractive method to strategically sensitize breast tumors to multiple immunotherapies. Citation Format: Ryuhjin Ahn, Kévin Jacquet, Marc Fabian, Sidong Huang, Nicolas Bisson, Josie Ursini-Siegel. The Shc1 scaffold protein simultaneously balances Stat1 and Stat3 activity in breast cancer to promote immune suppression and resistance to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3981. doi:10.1158/1538-7445.AM2017-3981
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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 | 0.000 |
| 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".