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Longitudinal plasma proteomic analysis identifies biomarkers and combinational targets for anti-PD1-resistant cancer
Qiaoyun Tan1, Ruyun Gao1, Xiaomei Zhang2
1Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study On Anticancer Molecular Targeted Drugs, Beijing, 100021, China.
Abstract:
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.
Insights
This study analyzed plasma proteomic changes in cancer patients receiving anti-PD1 therapy. It identified biomarkers and pathways linked to treatment response, offering new strategies for resistant cases.
Area of Science:
- Oncology
- Proteomics
- Immunotherapy
Background:
- Anti-PD1 therapy response rates are limited, and its impact on cancer patients remains unclear.
- Understanding proteomic changes can elucidate treatment mechanisms and resistance.
- Non-small cell lung cancer (NSCLC), alveolar soft part sarcoma (ASPS), and lymphoma are key cancer types studied.
Purpose of the Study:
- To conduct a longitudinal plasma proteomic analysis of anti-PD1 therapy in NSCLC, ASPS, and lymphoma.
- To identify differential proteomic characteristics between responders and non-responders.
- To discover novel therapeutic targets and noninvasive biomarkers for anti-PD1 therapy.
Main Methods:
- Longitudinal analysis of 339 plasma samples from 193 patients before and after anti-PD1 therapy.
- Plasma protein detection using data-independent acquisition-mass spectrometry and antibody microarrays.
- Differential proteomic expression analysis between responder and non-responder groups.
Main Results:
- 1019 proteins were detected; 50, 206, and 268 differentially expressed proteins were identified in NSCLC, ASPS, and lymphoma, respectively.
- Upregulated pathways in non-responders included Th17, IL-17, and JAK-STAT; responders showed activated cellular senescence and transcriptional misregulation.
- Longitudinal analysis revealed IL-17 pathway downregulation post-treatment; several proteins (e.g., IL-17A, CD22) identified as potential combinatorial targets.
- Validated noninvasive biomarkers include FLT4, SFTPB, GNPTG, F5, IL-17A in lymphoma, and KIT, CCL3, TNFSF1 in NSCLC.
Conclusions:
- Plasma proteomic profiling provides molecular insights into anti-PD1 therapy efficacy.
- Identified pathways and proteins offer potential therapeutic strategies for anti-PD1-resistant cancers.
- Validated noninvasive biomarkers can aid in patient stratification and treatment monitoring.
