Immune landscape and prognostic immune-related genes in KRAS-mutant colorectal cancer patients

Jungang Liu,Xiaoliang Huang,Haiquan Qin,Haizhou Liu,Guo Wu,Yongsheng Meng,Yawei Zhang,Xianwei Mo,Weizhong Tang,Weishun Xie,Haiming Ru,Chunyin Wei,Caroline H Johnson,Hao Lai

doi:10.1186/s12967-020-02638-9

Abstract

BackgroundKRAS gene is the most common type of mutation reported in colorectal cancer (CRC). KRAS mutation-mediated regulation of immunophenotype and immune pathways in CRC remains to be elucidated.Methods535 CRC patients were used to compare the expression of immune-related genes (IRGs) and the abundance of tumor-infiltrating immune cells (TIICs) in the tumor microenvironment between KRAS-mutant and KRAS wild-type CRC patients. An independent dataset included 566 cases of CRC and an in-house RNA sequencing dataset were served as validation sets. An in-house dataset consisting of 335 CRC patients were used to analyze systemic immune and inflammatory state in the presence of KRAS mutation. An immue risk (Imm-R) model consist of IRG and TIICs for prognostic prediction in KRAS-mutant CRC patients was established and validated.ResultsNF-κB and T-cell receptor signaling pathways were significantly inhibited in KRAS-mutant CRC patients. Regulatory T cells (Tregs) was increased while macrophage M1 and activated CD4 memory T cell was decreased in KRAS-mutant CRC. Prognosis correlated with enhanced Tregs, macrophage M1 and activated CD4 memory T cell and was validated. Serum levels of hypersensitive C-reactive protein (hs-CRP), CRP, and IgM were significantly decreased in KRAS-mutant compared to KRAS wild-type CRC patients. An immune risk model composed of VGF, RLN3, CT45A1 and TIICs signature classified CRC patients with distinct clinical outcomes.ConclusionsKRAS mutation in CRC was associated with suppressed immune pathways and immune infiltration. The aberrant immune pathways and immune cells help to understand the tumor immune microenvironments in KRAS-mutant CRC patients.

Highlights

Kirsten rat sarcoma viral oncogene homolog (KRAS) gene is the most common type of mutation reported in colorectal cancer (CRC)
The most frequent mutation seen in CRC was in the adenomatous polyposis coli (APC) gene (79%) followed by the tumor protein 53 (TP53) gene (61%)
We compared the frequency of gene mutations between the two groups and found that mutation frequency of APC and PIK3CA was significantly increased in the KRAS mutant group, while mutation frequency of TP53 and ZFHX4 was significantly increased in the KRAS wildtype group (Fig. 1b)

Summary

Introduction

KRAS gene is the most common type of mutation reported in colorectal cancer (CRC). KRAS mutationmediated regulation of immunophenotype and immune pathways in CRC remains to be elucidated. Colorectal cancer (CRC) remains a major cause of cancer-related mortality worldwide despite advancements in tumor screening, early diagnosis, and curative resection. 20–25% of CRC patients show evidence of metastatic disease with no scope for radical surgery [1]. Treatment regimens combining cytotoxic chemotherapy and biological agents improved overall survival of patients with metastatic CRC by more than two years [3]. The advent of immunotherapy further advanced the scope of prolonging survival in cancer patients. Immune checkpoint blockade therapy has shown promising therapeutic results in patients with advanced malignant tumor, such as non-small cell lung cancer, melanoma, renal cell carcinoma, and mismatch repair-deficient tumors [4, 5]. Since the majority of CRC patients are microsatellite-stable, researching the immune microenvironment and identifying potential immunotherapeutic targets are important in improving the effectiveness of immunotherapy in these patients

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