(1) Kong J (2) Zhao X (3) Singhal A (4) Park S (5) Bachelder R (6) Shen J (7) Zhang H (8) Moon J (9) Ahn C (10) Ock CY (11) Carter H (12) Ideker T

Science advances | Free PMC Article

While immune checkpoint inhibitors have revolutionized cancer therapy, many patients exhibit poor outcomes. Here, we show immunotherapy responses in bladder and non-small cell lung cancers are effectively predicted by factoring tumor mutation burden (TMB) into burdens on specific protein assemblies. This approach identifies 13 protein assemblies for which the assembly-level mutation burden (AMB) predicts treatment outcomes, which can be combined to powerfully separate responders from nonresponders in multiple cohorts (e.g., 76% versus 37% bladder cancer 1-year survival). These results are corroborated by (i) engineered disruptions in the predictive assemblies, which modulate immunotherapy response in mice, and (ii) histochemistry showing that predicted responders have elevated inflammation. The 13 assemblies have diverse roles in DNA damage checkpoints, oxidative stress, or Janus kinase/signal transducers and activators of transcription signaling and include unexpected genes (e.g., PIK3CG and FOXP1) for which mutation affects treatment response. This study provides a roadmap for using tumor cell biology to factor mutational effects on immune response.

Author Info: (1) Department of Medicine and Moores Cancer Center, School of Medicine, University of California San Diego, San Diego, CA, USA. (2) Department of Medicine and Moores Cancer Center

Author Info: (1) Department of Medicine and Moores Cancer Center, School of Medicine, University of California San Diego, San Diego, CA, USA. (2) Department of Medicine and Moores Cancer Center, School of Medicine, University of California San Diego, San Diego, CA, USA. (3) Department of Computer Science and Engineering, University of California San Diego, San Diego, CA, USA. (4) Department of Medicine and Moores Cancer Center, School of Medicine, University of California San Diego, San Diego, CA, USA. (5) Department of Medicine and Moores Cancer Center, School of Medicine, University of California San Diego, San Diego, CA, USA. (6) Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. (7) Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. (8) Lunit Incorporated, Seoul, South Korea. (9) Lunit Incorporated, Seoul, South Korea. (10) Lunit Incorporated, Seoul, South Korea. (11) Department of Medicine and Moores Cancer Center, School of Medicine, University of California San Diego, San Diego, CA, USA. (12) Department of Medicine and Moores Cancer Center, School of Medicine, University of California San Diego, San Diego, CA, USA. Department of Computer Science and Engineering, University of California San Diego, San Diego, CA, USA. Department of Bioengineering, University of California San Diego, San Diego, CA, USA.

Citation: Sci Adv 2024 Sep 20 10:eado9746 Epub09/20/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39303028

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