The immune response to colorectal cancer: implications for prognosis

[Truncated abstract] It has been known for several decades that infiltration of colorectal cancers (CRCs) by host immune cells is beneficial. More recently it has been demonstrated that specific immune cell subtypes have strong prognostic significance. Some authors, however, expressed the view that tumours may recruit inhibitory immune cells (Tregs – T regulatory cells) to suppress the anti-tumour host response. As yet, however, measurement of immune cells has not come into routine practice and tumour-node-metastasis (TNM) remains the gold standard for prognostication. This generally serves us well; however, robust markers are required for the identification of high risk stage II CRC patients whose survival is highly variable and in whom the benefits of adjuvant chemotherapy are uncertain. Aims: To identify and quantify previously examined immune cells (CD8+ and CD45RO+ T cells) within CRC that were previously known to confer a beneficial prognostic effect. To identify and quantify Tregs and investigate their prognostic significance within CRC. To compare the prognostic significance of Tregs with the active component (GrB – Granzyme B) of CD8+ T cells. To validate the prognostic significance of tumour-infiltrating Tregs on a separate patient cohort of stage II colon cancer. To investigate the prognostic significance of immune markers within histologically normal mucosa taken from the surgical margin of stage II colon cancers. Methods: Immune markers were identified with immunohistochemistry (IHC) and quantified using digital image analysis. Aims 1-3 were performed on a tissue microarray (TMA) consisting of tumour cores from 967 patients with stage II and III CRC. Aims 4-5 were performed on “full face sections” from independent cohort of 165 patients with colon cancer who did not receive adjuvant chemotherapy. Results Chapter 3 (Aims 1-2) CD8+ and CD45RO+ T cells no longer retained prognostic significance when the density of Tregs were assessed.