T-cell CX3CR1 expression as a dynamic blood-based biomarker of response to immune checkpoint inhibitors

Immune checkpoint inhibitors (ICI) have revolutionized treatment for various cancers; however, durable response is limited to only a subset of patients. Discovery of blood-based biomarkers that reflect dynamic change of the tumor microenvironment, and predict response to ICI, will markedly improve current treatment regimens. Here, we investigate CX3C chemokine receptor 1 (CX3CR1), a marker of T-cell differentiation, as a predictive correlate of response to ICI therapy. Successful treatment of tumor-bearing mice with ICI increases the frequency and T-cell receptor clonality of the peripheral CX3CR1(+)CD8(+) T-cell subset that includes an enriched repertoire of tumor-specific and tumor-infiltrating CD8(+) T cells. Furthermore, an increase in the frequency of the CX3CR1(+) subset in circulating CD8(+) T cells early after initiation of anti-PD-1 therapy correlates with response and survival in patients with non-small cell lung cancer. Collectively, these data support T-cell CX3CR1 expression as a blood-based dynamic early on-treatment predictor of response to ICI therapy. There is an urgent need to discover blood-based biomarkers to predict response to immune checkpoint inhibitors (ICI). Here the authors show that effective ICI therapy correlates with increased frequency of circulating CX3CR1(+)CD8(+) T cells in preclinical tumor models and in a cohort of patients with non-small cell lung cancer treated with anti-PD-1.