Mismatch repair gene defects in sporadic colorectal cancer enhance immune surveillance

Abstract

BackgroundThere is evidence that colorectal cancers (CRC) with DNA mismatch repair deficiency (MMR-D) are associated with a better prognosis than the generality of large bowel malignancies. Since an active immune surveillance process has been demonstrated to influence CRC outcome, we investigated whether MMR-D can enhance the immune response in CRC.Patients and MethodsA group of 113 consecutive patients operated for CRC (42 stage I or II and 71 with stage III or IV) was retrospectively analyzed. The expression of MMR genes (MSH2, MLH1, MSH6 and PSM2) and co-stimulatory molecule CD80 was assessed by tissue microarray immunohistochemistry. In addition, tumor infiltrating mononuclear cells (TIMC) and T cell subpopulations (CD4, CD8, T-bet and FoxP-3) were quantified. The effect of specific siRNA (siMSH2, siMLH1, siMSH6 and siPSM2) transfection in HT29 on CD80 expression was quantified by flow cytometry. Non parametric statistics and survival analysis were used.ResultsPatients with MMR-D showed a higher T-bet/CD4 ratio (p = 0.02), a higher rate of CD80 expression and CD8 lymphocyte infiltration compared to those with no MMR-D. Moreover, in the MMR-D group, the Treg marker FoxP-3 was not expressed (p = 0.05). MMR-D patients with stage I or II and T-bet expression had a significant better survival (p = 0.009). Silencing of MSH2, MLH1 and MSH6, but not PSM2, significantly increased the rate of CD80+ HT29 cells (p = 0.007, p = 0.023 and p = 0.015, respectively).ConclusionsCRC with MMR-D showed a higher CD80 expression, and CD8+ and Th1 T-cell infiltration. In vitro silencing of MSH2, MLH1 and MSH6 significantly increased CD80+ cell rate. These results suggest an enhanced immune surveillance mechanism in presence of MMR-D.

Effects of immune suppression for transplantation on inflammatory colorectal cancer progression

“…Interestingly, our patient received a massive immunosuppressive load with anti-thymocyte globulins and a switch to a TAC plus MPS plus prednisone-based regimen after the episode of acute rejection, which occurred 6 months before the diagnosis of metastatic anal transitional zone adenocarcinoma. Moreover, this cancer showed an unexpected reduced T cell infiltration, contrary to what is usually observed in CRC with MMR defects or in UC-related CRC 19 , 20 . In fact, in our patient, CD4 and CD8 infiltration within the tumor was similar to that observed in post-transplant CRCs and lower than that observed in UC-related CRCs, suggesting a deep effect on cancer microenvironment of post-transplant immunosuppression regimen.…”

Intratumoral immune-biomarkers and mismatch repair status in leiyomyosarcoma -potential predictive markers for adjuvant treatment: a pilot study

“…The two patients whose tumors were MMR-D had unexpectedly sparse CD8 infiltration and a lack of PD-L1 expression. This is in contrast to reports on epithelial neoplasms where abundant CD8 infiltration was observed in MMR-D tumors such as colon, endometrial and gastric cancers [ 15 – 17 ].…”

PD‐L1 overexpression in ampulla of Vater carcinoma and its pre‐invasive lesions

“…MMRd tumours have been demonstrated to be frequently PD‐L1‐positive . This could be explained by the characteristic accumulation of mutations in MMRd tumours, which results in the acquisition of unknown novel epitopes and the excessive activation of the immune system leading to the instigation of immunomodulatory mechanisms . Alterations in the MMR machinery are relatively frequent among AVCs, especially in the intestinal type .…”