Immune response gene expression in colorectal cancer carries distinct prognostic implications according to tissue, stage and site: a prospective retrospective translational study in the context of a hellenic cooperative oncology group randomised trial

PLoS One. 2015 May 13;10(5):e0124612. doi: 10.1371/journal.pone.0124612. eCollection 2015.

Abstract

Background: Although host immune response is an emerging prognostic factor for colorectal cancer, there is no consensus on the optimal methodology, surrogate markers or tissue for study.

Patients and methods: Tumour blocks were prospectively collected from 344 patients with stage II/III colorectal cancer (CRC) treated with adjuvant chemotherapy. Whole section lymphocytic infiltration was studied along with mRNA expression of CD3Z, CD8, CD4, CXCL9, CXCL13, IGHM, FOXP3, SNAI2 and ESR1 by qRT-qPCR in tissue microarray (TMA) cores from the centre of tumour, invasive margin and adjacent normal mucosa.

Results: Lymphocytic infiltration, deficient MMR (10.9%), KRAS (40.7%) and BRAF (4.9%) mutations or single mRNA gene expression were not prognostic. Tumour ESR1 gene expression (Hazard Ratio [HR] for relapse 2.33, 95% CI 1.35-4.02; HR for death 1.74, 95% CI 1.02-2.97) and absence of necrosis (HR for relapse 1.71, 95% CI 1.05-2.71; HR for death 1.98, 95% CI 1.14-3.43) were adverse prognostic features. We used CD3Z and CD8 expression in order to devise the mRNA-based Immune Score (mIS) and proceeded to partitioning analysis in 267 patients, with age, stage, tumour site (Right vs Left CRC), KRAS mutation and tumour mIS as input factors. Only in patients with stage III right-sided colon cancer, a low immune response was associated with inferior disease-free survival (mIS-low, HR for relapse 2.28, 95% CI 1.05-8.02). No prognostic significance was seen for tumour mIS in any other stage or site of CRC, or for a similar mIS score derived from adjacent normal mucosa. Independent adverse prognostic significance was retained in multivariable analysis for absence of necrosis, tumour ESR1 expression in all patients and low tumour mIS in stage III right-sided CRC.

Conclusions: In localised CRC, mRNA-based CD3Z/CD8 profiling of tumour immune response may have stage, site and tissue-specific prognostic significance, along with ESR1 expression.

Trial registration: ANZCTR.org.au ACTRN12610000509066.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / diagnosis
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / immunology
  • Adenocarcinoma / mortality
  • Adult
  • Age Factors
  • Aged
  • Antigens, CD / genetics*
  • Antigens, CD / immunology
  • Chemokines, CXC / genetics
  • Chemokines, CXC / immunology
  • Colorectal Neoplasms / diagnosis
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / mortality
  • Estrogen Receptor alpha / genetics*
  • Estrogen Receptor alpha / immunology
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Heterozygote*
  • Humans
  • Immunity, Innate
  • Lymphatic Metastasis
  • Male
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / immunology
  • Neoplasm Staging
  • Prognosis
  • Prospective Studies
  • Retrospective Studies
  • Survival Analysis
  • Tissue Array Analysis
  • Transcription Factors / genetics
  • Transcription Factors / immunology

Substances

  • Antigens, CD
  • Chemokines, CXC
  • Estrogen Receptor alpha
  • Neoplasm Proteins
  • Transcription Factors
  • estrogen receptor alpha, human

Associated data

  • ANZCTR/ACTRN12610000509066

Grant support

This research project was supported by an unrestricted research grant from the Hellenic Foundation for Cancer Research (HeFCR) and the Hellenic Cooperative Oncology Group (HeCOG) (HER6C05). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.