🧵1/.Tumor aneuploidy—long viewed as a hallmark of cancer—is emerging as a key biomarker of immune resistance. In our latest @NatureGenet Perspective, we explore how aneuploidy can guide immunotherapy decisions and shape future treatment strategies. 🔗

RT @Cancer_Cell: Online Now: The dark side of radiotherapy

RT @UCCancerCenter: Check out the excellent perspective published by Sean Pitroda, MD, and colleagues in @NatureGenet, highlighting how hig….

📢 New in Cancer Cell: Radiotherapy is essential for local control—but can it unintentionally accelerate growth of distant metastases? We examine how RT-induced EGFR signaling and immune modulation may fuel metastatic progression. 🧠🧬🔬.Read:

RT @SeanPitroda: 10/.Read the full Perspective by Daniel Huang, @liamspurr, @rweichselbaum, and @SeanPitroda .👉 Let….

RT @SeanPitroda: 11/.Special thanks to @UCCancerCenter @UChicagoMed @UChicago @UChicagoRadonc @Ludwig_Cancer @LUNGevity.

RT @SeanPitroda: 12/.Also, thanks to @UChicagoMed for highlighting our work!.

12/.Also, thanks to @UChicagoMed for highlighting our work!.

RT @SeanPitroda: 🧵1/.Tumor aneuploidy—long viewed as a hallmark of cancer—is emerging as a key biomarker of immune resistance. In our lates….

RT @UCCancerCenter: 🌟 In a new study, Huang et al., emphasizes on combining immunotherapy with radiation that may overcome therapy resistan….

RT @LiamSpurrMD: Check out our new perspective in @NatureGenet exploring the role of #aneuploidy in predicting outcomes following treatment….

11/.Special thanks to @UCCancerCenter @UChicagoMed @UChicago @UChicagoRadonc @Ludwig_Cancer @LUNGevity.

10/.Read the full Perspective by Daniel Huang, @liamspurr, @rweichselbaum, and @SeanPitroda .👉 Let’s bring tumor aneuploidy from bench to bedside. #oncology #immunotherapy #radiationoncology #precisionmedicine.

9/.Key takeaways:.🔹 Aneuploidy is a powerful biomarker—both prognostic & predictive.🔹 It can help personalize ICB-based therapy.🔹 Combining genomic features (aneuploidy, TMB, PD-L1) is the future.🔹 Prospective trials incorporating aneuploidy are urgently needed.

8/.Why it matters:.✔️ Aneuploidy is quantifiable from genomic data.✔️ Independent of TMB/PD-L1.✔️ Guides treatment escalation (e.g., SABR, dual-ICB).✔️ May help identify patients for de-escalation too.📌Aneuploidy isn’t just noise—it's clinically actionable signal.

7/.🧠 Aneuploid tumors are also biologically vulnerable. Example: CIN-high cancers depend on the mitotic motor protein KIF18A. Targeting this dependency (e.g., with KIF18A inhibitors) shows promise in preclinical models. This opens new therapeutic windows.

6/.Aneuploidy may inform treatment beyond metastatic settings:.➡️ Locally advanced NSCLC (PACIFIC regimen).➡️ Early-stage NSCLC (e.g., SABR + ICB trials).➡️ Neoadjuvant chemo-ICB strategies.Tailoring therapy intensity based on AS (aneuploidy score) could optimize outcomes.

5/.Current biomarkers like TMB and PD-L1 expression are imperfect. Aneuploidy adds unique value—especially when combined with TMB to improve prediction of ICB response. 🧪 Low aneuploidy + high TMB = best responders.⚠️ High aneuploidy alone = ICB resistance unless intensified tx.

4/.High aneuploidy = ICB resistance?.Yes—but not always irreversible. Our work in metastatic NSCLC shows adding stereotactic radiotherapy (SABR) to ICB overcomes resistance in highly aneuploid tumors. 🧬 Aneuploidy is predictive, not just prognostic.

3/.Aneuploidy suppresses antitumor immunity by:.🔹 Triggering proteotoxic stress.🔹 Polarizing macrophages to M2 phenotype.🔹 Activating (then suppressing) STING signaling.🔹 Reducing CD8+ T cell infiltration.(Fig. 1 below ⬇️).

2/.What is tumor aneuploidy?.➡️ It’s the gain/loss of whole chromosomes or arms—present in ~90% of solid tumors. 📉 Generally linked to worse prognosis. 🛡️ But also drives immune evasion and resistance to immune checkpoint blockade (ICB).