Serum test identifies patients deriving benefit from CPIs 189 5 Discussion Here, we report the establishment of a pretreatment serum proteomic classifier that separates those patients who obtain little from those that obtain durable clinical benefit from treatment with the PD-1 inhibitor nivolumab as second-line treatment for advanced NSCLC. Based on 274 MS features, patients could be classified as being resistant, intermediate or sensitive. The difference in OS between resistant and not resistant patients was highly significant: the HR was 0.48, and median survival times were 4.3 months vs 11.1 months, respectively. The test was validated while blinded to clinical outcome data with an independent set of advanced NSCLC patients, treated at a different institution. The classifier failed to stratify outcomes within a historical cohort of advanced NSCLC patients treated with docetaxel as secondline therapy. Moreover, test classification, as expected, was independent of wellestablished clinical factors and notably showed no evidence of association with PD-L1 expression. A serum test would have obvious advantages, such as ease of detection using one blood draw. Also, the test may avoid the issue of intra patient tumor heterogeneity and could assess host factors that are not captured by examination of the tumor microenvironment in histological samples. Further characterization of the classifier revealed that the classification phenotypes identified are associated with biological processes known to confer a poor prognosis in lung cancer. Several lines of research indicate that complement, as a member of a diverse family of innate immune proteins, is involved in dysregulation of mitogenic signaling and escape from immune surveillance27,28. Complement activation, as measured by Cd4, a stable complement degradation product, in serum of early-stage NSCLC patients was significantly associated with poor prognosis29. A number of authors have identified the ratio of the acute phase protein, serum C-Reactive Protein, to albumin as a negative prognostic factor in both early and advanced NSCLC30. Intratumoral wound healing signatures, as measured by mRNA expression arrays, are considered to be T-cell suppressive and have been observed in several tumor types, amongst them NSCLC31. Interestingly, sera derived from patients with tumors exhibiting wound healing signatures elicited identical signatures from non-tumor associated fibroblasts, which were found to be a powerful predictor of an unfavorable clinical course32. These observations may provide the biological basis of our findings, although a direct link between the abundance of these circulating proteins and absence of a response to PD-1 inhibitors remains to be established.
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