Abstract
Immune checkpoint blockade (ICB) of the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) immune checkpoint pathway has led to unprecedented advances in cancer therapy. However, the overall response rate of anti-PD-1/PD-L1 monotherapy is still unpromising, underscoring the need for predictive biomarkers. In this retrospective study, we collected pretreatment plasma samples from two independent cohorts of patients receiving ICB. To determine whether a signature of plasma cytokines could be associated with therapeutic efficacy, we systemically profiled cytokine clusters and functional groups in the discovery and validation datasets by using 59 multiplexed bead immunoassays and bioinformatics analysis. We first attempted to functionally classify the 59 immunological factors according to their biological classification or functional roles in the cancer-immunity cycle. Surprisingly, we observed that two signatures, the “checkpoint signature” and “trafficking of T-cell signature”, were higher in the response subgroup than in the nonresponse subgroup in both the discovery and validation cohorts. Moreover, enrichment of the “checkpoint signature” was correlated with improved overall survival and progression-free survival in both datasets. In addition, we demonstrated that increased baseline levels of three checkpoint molecules (PD-L1, T-cell immunoglobulin mucin receptor 3 and T-cell-specific surface glycoprotein CD28) were common peripheral responsive correlates in both cohorts, thus rendering this “refined checkpoint signature” an ideal candidate for future verification. In the peripheral blood system, the “refined checkpoint signature” may function as a potential biomarker for anti-PD-1/PD-L1 monotherapy in gastrointestinal (GI) cancers.
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Data availability
All data generated or analyzed during this study are included in this article [and its supplementary information files].
Abbreviations
- anti-PD-1:
-
Anti-programmed cell death 1
- BTLA:
-
B- and T-lymphocyte attenuator
- CNA:
-
Copy number alteration
- CD152:
-
Cluster of differentiation 152
- CR:
-
Complete response
- GEP:
-
Gene expression profiling
- GI:
-
Gastrointestinal
- ICB:
-
Immune checkpoint blockade
- ICI:
-
Immune checkpoint inhibitor
- IF:
-
Immunofluorescence
- IFNs:
-
Interferons; DCs, dendritic cells
- IL18:
-
Interleukin 18
- IL-2:
-
Interleukin-2
- LAG3:
-
Lymphocyte activation gene-3-protein
- mDCs:
-
Mature DCs
- MIF:
-
Migration inhibitory factor
- mIHC:
-
Multiplex immunohistochemistry
- MSI:
-
Microsatellite instability
- ORR:
-
Overall response rate
- OS:
-
Overall survival
- PD:
-
Progressive disease
- PD-L1:
-
Programmed cell death ligand 1
- PFS:
-
Progression-free survival
- PR:
-
Partial response
- RECIST:
-
Response Evaluation Criteria in Solid Tumors
- sCD28:
-
Soluble CD28
- SCLC:
-
Small cell lung cancer
- SD:
-
Standard deviation
- SD:
-
Stable disease
- sPD-L1:
-
Soluble PD-L1
- TGFβ:
-
Transforming growth factor β
- TILs:
-
Tumor infiltrating immune cells
- TIM3:
-
T-cell immunoglobulin mucin receptor 3
- TMB:
-
Tumor mutational burden
- TNFα:
-
Tumor necrosis factor α
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This work was supported by grant from the National Key Sci-Tech Special Project of China (No. 2018ZX10302207).
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This study was approved by the Internal Review and the Committee of the Fifth Medical Center, General Hospital of the PLA, Ethics Committee of Zhongshan Hospital Affiliated to Fudan University and was performed in accordance with the Declaration of HELSINKI.
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Zhao, C., Wu, L., Liang, D. et al. Identification of immune checkpoint and cytokine signatures associated with the response to immune checkpoint blockade in gastrointestinal cancers. Cancer Immunol Immunother 70, 2669–2679 (2021). https://doi.org/10.1007/s00262-021-02878-8
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DOI: https://doi.org/10.1007/s00262-021-02878-8