Prognostic impacts of tumoral expression and serum levels of PD-L1 and CTLA-4 in colorectal cancer patients

Cancer Immunol Immunother. 2020 Dec;69(12):2533-2546. doi: 10.1007/s00262-020-02645-1. Epub 2020 Jun 23.

Abstract

Background: Programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) play a pivotal role in cancer immunotherapy. Each of these molecules has a membrane-bound receptor form (mPD-L1/mCTLA-4) and a soluble form (sPD-L1/sCTLA-4). However, these prognostic impacts in colorectal cancer (CRC) remain unclear.

Methods: We immunohistochemically scored tumoral mPD-L1/mCTLA-4 expression and quantified preoperative circulating sPD-L1/sCTLA-4 levels using matched serum specimens from 131 patients with pStage I-III CRC. We also examined the association between these statuses and tumor infiltrating lymphocytes (TILs) in these patients.

Results: Elevated levels of mPD-L1, mCTLA-4, sPD-L1 and sCTLA-4 were significantly correlated with poor overall survival (OS) and disease-free survival (DFS). Co-high expression of tumoral mPD-L1 and mCTLA-4 or co-elevated levels of serum sPD-L1 and sCTLA-4 were strongly correlated with poor OS and DFS. Multivariate analysis revealed that both statuses were negative independent prognostic factors for OS [hazard ratio (HR) 3.86, 95% confidence interval (95% CI) 1.71-8.51, p = 0.001; HR 5.72, 95% CI 1.87-14.54, p = 0.004, respectively] and DFS (HR 2.53, 95% CI 1.23-4.95, p = 0.01; HR 6.88, 95% CI 2.42-17.13, p = 0.0008, respectively). Although low expression of tumoral mCTLA-4 was significantly correlated with increased CD8(+) TILs, there was no correlation in any other combination.

Conclusions: We verified the prognostic impacts of mPD-L1, mCTLA-4, sPD-L1 and sCTLA-4 in pStage I-III CRC patients. Dual evaluation of immune checkpoint molecules in primary tissues or preoperative serum could identify a patient population with poor prognosis in these patients.

Keywords: CTLA-4; Colorectal Cancer; PD-L1; Soluble receptors and ligands; Tumoral membrane expression.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • B7-H1 Antigen / blood
  • B7-H1 Antigen / immunology
  • B7-H1 Antigen / metabolism*
  • Biomarkers, Tumor / blood
  • Biomarkers, Tumor / immunology
  • Biomarkers, Tumor / metabolism*
  • CTLA-4 Antigen / blood
  • CTLA-4 Antigen / immunology
  • CTLA-4 Antigen / metabolism*
  • Colon / immunology
  • Colon / pathology
  • Colon / surgery
  • Colorectal Neoplasms / blood
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / mortality*
  • Colorectal Neoplasms / surgery
  • Disease-Free Survival
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Prognosis
  • Rectum / immunology
  • Rectum / pathology
  • Rectum / surgery
  • Retrospective Studies

Substances

  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • CTLA-4 Antigen
  • CTLA4 protein, human