Identification of immune checkpoint and cytokine signatures associated with the response to immune checkpoint blockade in gastrointestinal cancers

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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Funding

This work was supported by grant from the National Key Sci-Tech Special Project of China (No. 2018ZX10302207).

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Correspondence to Yiyi Yu or Henghui Zhang or Jianming Xu.

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The authors declare that they have no conflict of interest.

Ethical approval

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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Informed consent was obtained from each patient before sample collection.

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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 (2021). https://doi.org/10.1007/s00262-021-02878-8

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Keywords

  • Immune checkpoint blockade
  • Predictive biomarker
  • Cytokine
  • Programmed cell death ligand 1
  • Biomarker