CD8 down-regulation on cytotoxic T lymphocytes of patients with endometrioid endometrial carcinomas

Hum Pathol. 2016 Oct;56:180-8. doi: 10.1016/j.humpath.2016.05.025. Epub 2016 Jun 23.

Abstract

Carcinogenesis is a multistep process in which cancer cells and tumor stroma cells play important roles. T lymphocytes are immune constituents of tumor stroma and play a crucial function in anti-tumor response. By immunohistochemistry and flow cytometry, we studied T cytotoxic (CTLs) and T helper lymphocyte distribution and percentage in the tumor microenvironment and peripheral blood from 35 patients with endometrioid endometrial carcinomas (EEC). We also studied 23 healthy donors' blood samples as a control group. Tumor and non-tumoral endometrium samples were obtained. Immunohistochemistry revealed a high number of CTLs and T helper lymphocytes in the tumor stroma of myoinvasive EECs. T lymphocytes were mostly located in the invasive front. By flow cytometry, the percentages of CTLs and T helper lymphocytes were significantly higher in the tumor compared with the non-neoplastic endometrium (P = .0492 and P = .002). The mean fluorescence intensity of CD8 staining was lower in the tumor compared to the non-neoplastic endometrium (P = .001). There was also reduction of the mean fluorescence intensity of CD8 staining on peripheral blood from patients with grade 3 EECs compare to the peripheral blood from healthy donors (P = .0093). No alterations in the expression of granzymes A and B were found in the CTLs from the EEC cases. Finally, in a proteome profiler cytokine array we found that the growth differentiation factor 15 (GDF15) increased in blood in parallel to the tumor grade. EECs are capable of down-regulating CD8 expression of CTLs. Most likely, this effect is mediated by a soluble molecule present in plasma and is not a result of anergy or exhaustion state.

Keywords: CD8; Endometrial carcinoma; Flow cytometry; GDF15; T lymphocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / analysis*
  • Biomarkers, Tumor / blood
  • CD8 Antigens / analysis*
  • Carcinoma, Endometrioid / blood
  • Carcinoma, Endometrioid / immunology*
  • Carcinoma, Endometrioid / pathology
  • Cytokines / blood
  • Down-Regulation
  • Endometrial Neoplasms / blood
  • Endometrial Neoplasms / immunology*
  • Endometrial Neoplasms / pathology
  • Female
  • Growth Differentiation Factor 15 / blood
  • Humans
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Middle Aged
  • Neoplasm Grading
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / pathology
  • Tumor Microenvironment

Substances

  • Biomarkers, Tumor
  • CD8 Antigens
  • Cytokines
  • GDF15 protein, human
  • Growth Differentiation Factor 15