Inflammatory and subtype-dependent serum protein signatures predict survival beyond the ctDNA in aggressive B cell lymphomas

Biological heterogeneity of large B cell lymphomas (LBCLs) is poorly captured by current prognostic tools, hampering optimal treatment decisions. We dissected the levels of 1,463 serum proteins in a uniformly treated trial cohort of 109 patients with high-risk primary LBCL (ClinicalTrials.gov: NCT01325194) and correlated the profiles with molecular data from tumor tissue and circulating tumor DNA (ctDNA) together with clinical data. We discovered clinically and biologically relevant associations beyond established clinical estimates and ctDNA. We identified an inflamed serum protein profile, which reflected host response to lymphoma, associated with inflamed and exhausted tumor microenvironment features and high ctDNA burden, and translated to poor outcome. We composed an inflammation score based on the identified inflammatory proteins and used the score to predict survival in an independent LBCL trial cohort (ClinicalTrials.gov: NCT03293173). Furthermore, joint analyses with ctDNA uncovered multiple serum proteins that correlate with tumor burden. We found that SERPINA9, TACI, and TARC complement minimally invasive subtype profiling and that TACI and TARC can be used to evaluate treatment response in a subtype-dependent manner in the liquid biopsy. Altogether, we discovered distinct serum protein landscapes that dissect the heterogeneity of LBCLs and provide agile, minimally invasive tools for precision oncology. This research was funded by grants from the Research Council of Finland, Finnish Cancer Organizations, Sigrid Juselius Foundation, University of Helsinki, iCAN Digital Precision Cancer Medicine Flagship, Orion Research Foundation sr, and Helsinki University Hospital. [Display omitted] •Landscape of 1,463 serum proteins in high-risk large B cell lymphoma (LBCL)•Inflamed serum protein profile predicts poor survival in primary LBCL•Several serum proteins complement circulating tumor DNA assessment•Lymphoma subtype marker proteins can be used to estimate response to therapy Clinical and biological heterogeneity remains a challenge for improving large B cell lymphoma (LBCL) survival. Here, by exploring the landscape of 1,463 serum proteins, Arffman et al. found an inflammatory profile that was associated with aggressive clinical characteristics, exhausted tumor microenvironment, and high circulating tumor DNA (ctDNA) levels. Furthermore, they show that multiple serum proteins have complementary potential together with ctDNA in subtype classification a