The Relationship Between Soluble PD-L1 and Viral Infection, ACR, and CLAD

Abstract

<h3>Purpose</h3> Respiratory viral infection (RVI) after lung transplant (LTx) is a risk factor for chronic lung allograft dysfunction (CLAD), but the mechanisms underlying this association are poorly understood. PD-L1 plays a key role in the normal host immune response to viruses. We hypothesized soluble PD-L1 (sPD-L1) levels are higher in subjects with RVI vs. acute cellular rejection (ACR), and that these levels may risk stratify patients for the development of CLAD. <h3>Methods</h3> We conducted a retrospective cohort study of LTx recipients with serum collected at the time of suspicion for RVI or ACR. At the time of sampling, 40 subjects had RVI and 27 subjects had ACR without RVI. We compared sPD-L1 levels between groups and tested for associations with the development of CLAD by 1-year post-infection. We are validating our findings in a prospective cohort that is enrolling subjects undergoing for-cause bronchoscopy with RVI (n = 7), ACR without RVI (n = 21), and without RVI or ACR (n = 22) with paired plasma and bronchoalveolar lavage fluid (BALF). <h3>Results</h3> In the retrospective cohort, subjects with RVI had 1.73-fold (95% CI 1.4 - 2.1) higher levels of serum sPD-L1 levels vs. subjects with ACR (without RVI) (p < 0.01). Doubling of serum sPD-L1 levels in subjects with RVI was associated with a higher risk for CLAD by 1-year post-infection (RR 4.96, 95% CI 1.64 - 15.0, p < 0.01, adjusting for age and sex). In contrast, there was no association between sPD-L1 levels at ACR (without RVI) and development of CLAD (RR 0.63, 95% CI 0.2 - 2.6, p = 0.50). In the prospective cohort, subjects with RVI again had significantly higher median plasma sPD-L1 levels (270 pg/ml) vs. subjects with ACR (without RVI) (173 pg/ml) (p < 0.01). Subjects without RVI or ACR had plasma values that were in between these two groups (median 222 pg/ml). BALF concentrations of sPD-L1 were not different between subjects in the 3 groups (beta: -0.1, p = 0.84) despite significant differences in the plasma (beta: -0.63, p < 0.01). <h3>Conclusion</h3> Higher levels of sPD-L1 at the time of RVI were associated with a higher risk for CLAD by 1-year post-infection. We are validating these findings prospectively, where peripheral blood (but not BALF) levels of sPD-L1 are significantly higher in subjects with RVI vs. ACR (without RVI). Our findings suggest PD-L1 may play divergent roles in the development of CLAD in two populations with key risk factors (RVI and ACR) for poor outcomes following LTx.