Abstract
BackgroundAlthough 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 MethodsTumour 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.ResultsLymphocytic 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.ConclusionsIn 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 RegistrationANZCTR.org.au ACTRN12610000509066
Highlights
Colorectal cancer (CRC) is the second cause of cancer death in the Western world
In patients with stage III right-sided colon cancer, a low immune response was associated with inferior disease-free survival
No prognostic significance was seen for tumour mRNA-based Immune Score (mIS) in any other stage or site of CRC, or for a similar mIS score derived from adjacent normal mucosa
Summary
Colorectal cancer (CRC) is the second cause of cancer death in the Western world. In Europe, 376000 new cases of colorectal cancer are diagnosed each year, with mortality observed in 204000 patients[1]. Over the last decade, published evidence suggests that outcomes in colorectal cancer are not solely dependent on tumour characteristics, and on the interactions between host and malignancy. The host immune response against the tumour is a finely tuned, multicellular and humoral reaction, emerging as an important factor for shaping the tumour-microenvironment interactions and for defining patient prognosis [2]. Controversy still persists on the ideal immune response markers to be followed, the tissue for study, the optimal methodology to be used and most importantly, the independent prognostic significance of tumour-associated immune reaction in relation to other clinicopathological and molecular variables[3]. 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
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