Prevalence of PD-L1 expression is associated with EMAST, density of peritumoral T-cells and recurrence-free survival in operable non-metastatic colorectal cancer

Abstract

Introduction Microsatellite instability (MSI) predict response to anti-PD1 immunotherapy in colorectal cancer (CRC). CRCs with MSI have higher infiltration of immune cells related to a better survival. Elevated Microsatellite Alterations at Tetranucleotides (EMAST) is a form of MSI but its association with PD-L1 expression and immune-cell infiltration is not known. Methods A consecutive, observational cohort of patients undergoing surgery for CRC. EMAST and clinicopathological characteristics were investigated against PD-L1, as well as CD3 and CD8 expression in the invasive margin or tumour centre (Immunoscore). Difference in survival between groups was assessed by log rank test. Results A total of 149 stage I-III CRCs patients, with a median follow up of 60.1 months. Patients with PD-L1+ tumours (7%) were older (median 79 vs 71 years, p = 0.045) and had EMAST+ cancers (OR 10.7, 95% CI 2.2-51.4, p = 0.001). Recurrence-free survival was longer in cancers with PD-L1+ immune cells (HR 0.35, 95% CI 0.16-0.76, p = 0.008, independent of EMAST) and high Immunoscore (HR 0.10, 95% CI 0.01-0.72, p = 0.022). Patients expressing PD-L1 in immune cells had longer disease-specific survival (HR 0.28, 95% CI 0.10-0.77, p = 0.014). Conclusions Higher Immunoscore (CD3/CD8 cells) and expression of tumour PD-L1 is found in CRCs with EMAST. Lymphocytic infiltrate and peritumoral PD-L1 expression have prognostic value in CRC.

Interplay of stromal tumor-infiltrating lymphocytes, normal colonic mucosa, cancer-associated fibroblasts, clinicopathological data and the immunoregulatory molecules of patients diagnosed with colorectal cancer

“…Cluster of differentiation 14 (CD14) is an important marker of macrophages that also serves important regulatory functions for monocytes when in soluble form [ 14 ]. Programmed cell death ligand-1 (PD-L1) is another crucial immune regulator in CRC that is actively released by both cancer and inflammatory cells and leads to T cell exhaustion, which has prognostic value [ 15 , 16 ]. The suppressive activity of inflammation is also regulated by the CD33 molecule, whose expression is specific for both myeloid and some subtypes of immune cells [ 17 ].…”

Elevated microsatellite instability at selected tetranucleotide (EMAST) repeats in gastric cancer: a distinct microsatellite instability type with potential clinical impact?

“…Again, the reasons for all these partially conflicting results may be related to the non‐standardised definition and determination of EMAST and differences in the study populations. A main reason, however, may be due to the fact that in some studies there is no concomitant analysis of MSI [ 29 ] or no clear separation of MSI‐H and EMAST positivity and hence no comparison of EMAST‐positive and ‐negative tumours in an MSS background [ 26 , 27 , 29 , 38 ]. Thus, certain patient characteristics that are known for MSI‐H are attributed to EMAST, which reflects essentially the same deficiency of the MMR machinery encompassing MLH1, MSH2, MSH6, and PMS2.…”

A template to quantify the location and density of CD3 + and CD8 + tumor-infiltrating lymphocytes in colon cancer by digital pathology on whole slides for an objective, standardized immune score assessment

“…All patients were diagnosed, managed and followed-up at Stavanger University Hospital (SUH), a public-funded university hospital within the universal health care system of Norway. The protocol [ 18 ] and study cohort have been described in further detail elsewhere [ 21 , 22 ]. The current study is based on patients with stage I–III colon cancer from the initial cohort recruited between January 2013 and May 2014 [ 21 ] that did not undergo neoadjuvant treatment.…”