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Immune Microenvironment in Colonic Carciongenesis: Sporadic Mismatch Repair Genes Defects Are Associated to Hicd80+ Lamina Propria Monuclear Cells Infiltration
Marco Scarpa*1, Cesare Ruffolo3, Fabio Canal3, Melania Scarpa1, Silvia Basato2, Francesca Erroi2, Andrea Porzionato2, Alain Fiorot3, Anna Pozza3, Ignazio Castagliuolo2, Nicolò Bassi3,2, Angelo Paolo Dei Tos3, Carlo Castoro1
1Oncological Surgery Unit, Veneto Institute of Oncology (IOV-IRCCS), Padova, Italy; 2University of Padova, Padova, Italy; 3Ospedale Regionale Cà Foncello, Treviso, Italy
BACKGROUND
Genomic defects in DNA mismatch repair (MMR) genes (MSH2, MLH1, PSM2 or MSH6) characterize the hereditary non polyposis colon cancer (HNPCC). However most colorectal cancers (CRC) with high-frequency microsatellite instability are sporadic, wherein the MMR defect develops because of inactivation of the MLH1 gene by DNA methylation. Multiple retrospective studies, including a population-based study and a meta-analysis, have demonstrated that patients with MMR-deficient colon cancers have a more favourable stage-adjusted prognosis compared with patients whose tumors have intact MMR. Since the immune environment of CRC has been demonstrated to influence its prognosis, we aimed to investigate the interplay between MMR genes and the immune environment in CRC
PATIENTS AND METHODS
A group of 98 consecutive patients operated on for colorectal cancer was retrospectively analysed. Familial and medical history were retrieved to assess the presence of Bethesda criteria for HNPCC diagnosis. Immunohistochemistry for CD80, TLR4, MyD88, MSH2, MLH1, MSH6 and PSM2 was performed on tissue sections. Moreover, lamina propria mononuclear cells (LPMC), polymorphonuclear cells and eosoinophil tumour infiltration was quantified. Patients were stratified in three groups: no MMR genes defect, MMR gene defects alone and MMR genes defects and at least one positive Bethesda criteria. Non parametric statistics was used.
RESULTS
In the three groups no difference was observed in term of polymorphonuclear cells and eosinophil infiltration and in term of TLR4 and MyD88 expression. On the contrary, LPMC infiltration was significantly higher in patients who had a MMR gene defect alone compared to patients who had no MMR genes defect and to those with MMR gene defect and positive Bethesda criteria (p=0.014). Similarly, a significantly higher frequency of patients with high CD80 expression was observed in patients who had a MMR genes defect alone compared to patients who had no MMR gene defect and to those with MMR genes defect and positive Bethesda criteria (p=0.048).
CONCLUSION
In patients with MMR defects and no Bethesda criteria for HNPCC antigen presenting cells function seems enhanced as shown by higher frequency of hiCD80+ patients and higher LPMC infiltration. This immune activation may play a role in the prognosis of these patients.
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