Coupling of response biomarkers between tumor and peripheral blood in patients undergoing chemoimmunotherapy

S ummary Platinum-based chemotherapy in combination with anti-PD-L1 antibodies has shown promising results in mesothelioma. However, the immunological mechanisms underlying its efficacy are not well understood and there are no predictive biomarkers to guide treatment decisions. Here, we combine time course RNA sequencing (RNA-seq) of peripheral blood mononuclear cells with pre-treatment tumor transcriptome data from the single-arm, phase 2 DREAM trial ( N = 54). Single-cell RNA-seq and T cell receptor sequencing (TCR-seq) reveal that CD8 + T effector memory (TEM) cells with stem-like properties are more abundant in peripheral blood of responders and that this population expands upon treatment. These peripheral blood changes are linked to the transcriptional state of the tumor microenvironment. Combining information from both compartments, rather than individually, is most predictive of response. Our study highlights complex interactions between the tumor and immune cells in peripheral blood during objective tumor responses to chemoimmunotherapy. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12616001170415. • Circulating CD8 + T EM s are more abundant in chemoimmunotherapy responders • These CD8 + T EM s show a progenitor-exhausted phenotype and stem-like properties • Stem-like CD8 + T EM expansion links to permissive pre-treatment tumor environment • Combining tumor and blood profiles improves chemoimmunotherapy response prediction Chin et al. analyze tumor and serial blood immune profiles in mesothelioma patients receiving chemoimmunotherapy. They identify stem-like CD8 + T effector memory cells associated with treatment response and demonstrate that combining peripheral blood and tumor data improves prediction of clinical outcome.