111P Adenosine pathway and exhaustion markers in peripheral T-cell correlate with benefit from immunotherapy in advanced non-small cell lung cancer

Anti-PD-1/PD-L1 therapy has been established as a standard of care in multiple settings in non-small cell lung cancer (NSCLC) treatment. However, many patients will not benefit from this treatment, and thus predictive biomarkers are urgently needed. Our aim was to identify biomarkers of benefit from immunotherapy evaluating T cell subpopulations in peripheral blood mononuclear cells (PBMCs). Patients with advanced NSCLC receiving anti-PD-1/PD-L1 therapy were identified and prospectively recruited. We explored differences in the baseline peripheral T cell phenotype between long-term responders (LTR) (defined as duration of response greater than or equal to 1 year) and non-responders (NR) (defined as a progressive disease in 3 months or less). PBMCs were isolated from pretreatment blood samples. Exhaustion, senescence, and adenosine signaling markers were evaluated in different T cell functional subsets by flow cytometry. In our cohort of 144 patients with NSCLC, we initially selected 9 NR and 10 LTR with available PBMCs samples. Males represented 77.8% and 80%, median age was 64.5 and 64.4 years and stage IV represented 55% and 60%, respectively. Median progression-free survival (mPFS) was 2.2 months for NR and was not-reached for the LTR group at a medium follow up time of 22 months. In the LTR group we found a significant increase of CD39+CD103+ cells percentages from total CD4+ (P=0.0014), total CD8+ (P=0.0153) T cells, and from central memory (CD4+CM) (P= 0.0093) and effector memory (CD4+EM ) (P=0.0070) subsets. These molecules identify exhausted T cells. LTR patients also showed CD8+CM cells co-expressing CD39+ and CD73+ (P=0.0031), which are adenosine-mediated immunosuppression markers. Additionally, CD27-CD28- from the EM re-expressing CD45RA subset (CD8+EMRA), considered as regulatory CD8+ T cells, also presented increased percentages in the LTR group (P=0.0133). Our results suggest that specific tumor experienced T cell subpopulations may be reactivated by anti-PD-1/PD-L1 therapy and recirculate in the periphery thus being useful predictors of long-term benefit from immunotherapy. We are currently validating these findings in the whole cohort.