Immune checkpoint blockade (ICB) has transformed cancer treatment, yet many patients still fail to respond, and the biological reasons behind this resistance remain unclear. Researchers have identified gene expression patterns associated with ICB outcomes, but distinguishing correlation from true causation has proven exceptionally difficult—especially in human tumors, where diverse cell types interact to shape therapeutic success. Dr. Baolin Liu, is developing an integrated, systems-level approach to uncover the genes and pathways that directly determine whether ICB succeeds or fails in melanoma, with the goal of revealing new therapeutic targets to overcome resistance.
Dr. Liu will begin by analyzing single-cell RNA-sequencing data from 400 melanoma tumors collected before and after ICB treatment, identifying cell types and gene programs associated with response or non-response. He will then combine this human dataset with a comprehensive suite of immune-relevant CRISPR screens, perturbation-response profiles, curated signaling pathways, and machine learning–based causal inference to pinpoint genes that causally regulate anti-tumor immune activity. By mapping both cell-intrinsic and cell-to-cell mechanisms—including pathways governing tumor cell killing, interferon signaling, antigen presentation, and immune suppression—he aims to determine how specific genes influence therapy outcomes. Top candidates will be experimentally validated to define their mechanisms and nominate new intervention strategies.
Dr. Liu brings deep expertise in single-cell analysis and immunotherapy research, including influential work identifying tumor-reactive CD8⁺ T cell states associated with ICB responsiveness across multiple cancer types. Building on this foundation, his research seeks to move beyond descriptive associations to uncover actionable mechanisms that explain why some tumors respond while others resist. By establishing a causal roadmap of ICB regulation in human melanoma, this work has the potential to guide more precise immunotherapies and improve outcomes for patients who currently derive limited benefit from existing treatments.
Sponsor
Nir Hacohen, PhD (Mentor); Caroline Uhler, PhD (Co-Mentor)
Projects and Grants
Dissecting causal regulators of response and resistance to checkpoint immunotherapy in human tumors
