Longitudinal plasma proteomic analysis identifies biomarkers and combinational targets for anti-PD1-resistant cancer patients

The response rate of anti-PD1 therapy is limited, and the influence of anti-PD1 therapy on cancer patients is unclear.

To address these challenges, we conducted a longitudinal analysis of plasma proteomic changes with anti-PD1 therapy in non-small cell lung cancer (NSCLC), alveolar soft part sarcoma (ASPS), and lymphoma patients.

We included 339 plasma samples before and after anti-PD1 therapy from 193 patients with NSCLC, ASPS, or lymphoma.

The plasma proteins were detected using data-independent acquisition-mass spectrometry and customable antibody microarrays.

Differential proteomic characteristics in responders (R) and non-responders (NR) before and after anti-PD1 therapy were elucidated.

A total of 1019 proteins were detected using our in-depth proteomics platform and distributed across 10–12 orders of abundance.

By comparing the differential plasma proteome expression between R and NR groups, 50, 206, and 268 proteins were identified in NSCLC, ASPS, and lymphoma patients, respectively.

Th17, IL-17, and JAK-STAT signal pathways were identified upregulated in NR group, while cellular senescence and transcriptional misregulation pathways were activated in R group.

Longitudinal proteomics analysis revealed the IL-17 signaling pathway was downregulated after treatment.

Consistently, many proteins were identified as potential combinatorial therapeutic targets (e.g., IL-17A and CD22).

Five noninvasive biomarkers (FLT4, SFTPB, GNPTG, F5, and IL-17A) were further validated in an independent lymphoma cohort ( n  = 39), and another three noninvasive biomarkers (KIT, CCL3, and TNFSF1) were validated in NSCLC cohort ( n  = 76).

Our results provide molecular insights into the anti-PD1 therapy in cancer patients and identify new therapeutic strategies for anti-PD1-resistant patients.