Five latent factors underlie response to immunotherapy.

Area of Science:

• Oncology
• Immunotherapy
• Biomarker Discovery

Background:

• Immune checkpoint inhibitors (CPIs) improve cancer treatment outcomes for a subset of patients.
• Predicting CPI response remains a significant clinical challenge.
• Existing biomarkers may overlap, obscuring independent predictive factors.

Purpose of the Study:

• To identify independent biomarkers for predicting response and survival in patients treated with CPIs.
• To establish a framework for organizing knowledge on CPI response biomarkers.

Main Methods:

• Unbiased analysis of multi-omics data (genomics, transcriptomics) and clinical data from 479 metastatic cancer patients.
• Validation across six independent cohorts comprising 1,491 patients.

Main Results:

• Discovery of five orthogonal latent factors associated with CPI response and survival.
• These factors include tumor mutation burden, T-cell effective infiltration, TGF-beta activity, prior treatment, and tumor proliferative potential.
• The identified factors demonstrated consistent association across diverse tumor types and in validation cohorts.

Conclusions:

• The five identified latent factors provide a robust, independent set of predictors for CPI response and survival.
• This framework can help organize and advance the field of CPI biomarker research.
• Understanding these factors is crucial for optimizing immunotherapy strategies.