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Tumor immune microenvironment in cancer patients with leukocytosis

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Tumor-related leukocytosis (TRL) is correlated with poor survival in various types of cancers, but the microenvironment of TRL-associated human tumors has not been fully elucidated. Here, we aimed to characterize the immune microenvironment of cancer patients with TRL. The transcriptional signatures of tumor tissues obtained from cervical cancer patients with (TRLpos) and without TRL (TRLneg) were compared. As a surrogate for TRL diagnosis, a leukocytosis signature (LS) score was derived using genes differentially expressed between TRLpos and TRLneg tumors. The immunological profiles of patients in the TCGA database with high (LShigh) or low LS scores were compared. TRLpos tumors were transcriptionally distinct from TRLneg tumors, exhibiting up-regulation of radioresistance and down-regulation of adaptive immune response-related genes. In the TCGA cervical cancer cohort (n = 303), patients with high LS had inferior survival rates compared to those with low LS (P = 0.023). LShigh tumors were enriched in radioresistance, wound healing, and myeloid-derived suppressor cell (MDSC) signatures and had a higher infiltration of M2 macrophages and a lower infiltration of M1 macrophages and lymphocytes. LShigh tumors also expressed higher levels of CXCR2 chemokines, CSF2, and CSF3. In the pan-cancer cohort (n = 9984), LShigh tumors also exhibited poor survival, signatures of a suppressive immune microenvironment, and higher expression of CXCR2 chemokines. Our data provide evidence for a suppressive immune microenvironment in patients with TRL and suggest promising targets, such as the CXCR2 axis, for its therapeutic intervention.

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Abbreviations

BCR:

B cell receptor

DEG:

Differentially expressed gene

FFPE:

Formalin-fixed paraffin-embedded

G-CSF:

Granulocyte colony-stimulating factor

GSEA:

Gene set enrichment analysis

GM-CSF:

Granulocyte–macrophage colony-stimulating factor

GO:

Gene ontology

GSVA:

Gene set variation analysis

IFN:

Interferon

LS:

Leukocytosis signature

M-CSF:

Macrophage colony-stimulating factor

MDSC:

Myeloid-derived suppressor cells

NLR:

Neutrophil-to-lymphocyte ratio

PD-1:

Programmed death-1

TAM:

Tumor-associated macrophage

TCGA:

The cancer genome atlas

TCR:

T cell receptor

TGF:

Transforming growth factor

TRL:

Tumor-related leukocytosis

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Authors and Affiliations

  1. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea

    Kyung Hwan Kim & Nam Suk Sim

  2. Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea

    Kyung Hwan Kim, Jee Suk Chang & Yong Bae Kim

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Contributions

KHK and YBK contributed to the study concept and design. JSC and YBK involved in data acquisition. KHK, NSS, JSC, and YBK were involved in data analysis and interpretation. KHK drafted a preliminary version of the paper, and all authors reviewed and critically revised the manuscript.

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Correspondence to Yong Bae Kim.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Review Board of Severance Hospital (4-2015-0454) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Kim, K.H., Sim, N.S., Chang, J.S. et al. Tumor immune microenvironment in cancer patients with leukocytosis. Cancer Immunol Immunother 69, 1265–1277 (2020). https://doi.org/10.1007/s00262-020-02545-4

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