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Combined MEK/PD-L1 inhibition alters peripheral cytokines and lymphocyte populations correlating with improved clinical outcomes in advanced biliary tract cancer.

PURPOSE
Biliary tract cancers (BTCs) are aggressive malignancies refractory to chemotherapy and immunotherapy. MEK inhibitor (MEKi)-based regimens may have utility in this disease when combined with PD-L1 blockade. We hypothesize that dual MEK/PD-L1 inhibition alters circulating soluble and cellular immune mediators to improve clinical outcomes in patients with advanced BTC.


EXPERIMENTAL DESIGN
We examined immune features in peripheral blood from 77 patients with advanced BTC enrolled in a Phase II clinical trial investigating atezolizumab with or without cobimetinib. Plasma and PBMCs were isolated from whole blood to evaluate soluble factors and immune cell populations. Baseline blood samples were additionally compared with healthy donors to identify immune signatures unique to BTC.


RESULTS
At baseline, the soluble factors PDGF-BB, PlGF-1, IL-5, and IL-17A were elevated in BTC patients compared to healthy adult donors, and higher baseline frequencies of CD8+BTLA+ T cells correlated with better overall survival in this trial. There were also significant treatment-related alterations in several factors, including decreased PDGF-BB following combination treatment, that correlated with improved OS and PFS. Higher baseline levels of IL-23 and RANTES corresponded to improved clinical outcomes following combination treatment. Dual MEKi/PD-L1 inhibition increased populations of CD4+TIM3+ and decreased CD8+VISTA+ T cells, correlating with worse OS and better PFS, respectively.


CONCLUSIONS
This work represents a comprehensive analysis of peripheral immune features in BTC patients and systemic responses to dual MEK/PD-L1 inhibition. These data support further investigation to understand how MEKi combines with immunotherapeutic approaches to improve clinical outcomes for advanced BTC patients.