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Intratumoral CD8+ Lymphocyte Infiltration as a Prognostic Factor and Its Relationship With Cyclooxygenase 2 Expression and Microsatellite Instability in Endometrial Cancer
  1. Tomohiro Suemori, MD*,,
  2. Nobuyuki Susumu, MD, PhD*,
  3. Takashi Iwata, MD, PhD*,
  4. Kouji Banno, MD, PhD*,
  5. Wataru Yamagami, MD, PhD*,
  6. Akira Hirasawa, MD, PhD*,
  7. Kokichi Sugano, MD, PhD,
  8. Eri Matsumoto and
  9. Daisuke Aoki, MD, PhD*
  1. *Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo;
  2. Department of Pathology, Tochigiken Saiseikai Utsunomiya Hospital, Tochigi; and
  3. Oncogene Research Unit/Cancer Prevention Unit, Tochigi Cancer Center Research Institute, Tochigi, Japan.
  1. Address correspondence and reprint requests to Nobuyuki Susumu, MD, PhD, Department of Obstetrics and Gynecology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: susumu35{at}a6.keio.jp.

Abstract

Objective Microsatellite instability (MSI) is caused by a defective DNA mismatch repair system. Colorectal cancer in MSI-positive patients is characterized by an increased number of tumor-infiltrating lymphocytes. On the other hand, it has recently been reported that cyclooxygenase 2 (COX-2) suppresses antitumor immunity. The objectives of the present study were to clarify the relationships among MSI status, COX-2 expression, and antitumor immune status and to verify impact of these factors on the prognosis of endometrial cancer.

Methods The data of 123 patients with endometrial cancer were analyzed. The numbers of tumor-infiltrating CD8+ T lymphocytes within cancer cell nests (TILs), as a representative of the antitumor immunity, and COX-2 expression levels in the tumor cells were analyzed by immunohistochemical staining. Microsatellite instability was evaluated by polymerase chain reaction analysis for 11 markers. Fisher exact probability test, Kaplan-Meier method, and proportional hazards analysis were used for the statistical analyses.

Results The MSI-positive tumors showed significantly higher grades (G2 or G3) and significantly larger numbers of TILs than did the MSI-negative tumors. The COX-2–high group showed significantly fewer TILs than did the COX-2–low group. Multivariate analysis identified a low number of TILs (<10), positive lymph node involvement, and high tumor malignancy grade as factors independently associated with poor prognosis. The prognosis was significantly poorer in the patients with MSI-positive tumors with high COX-2 expression than in those with MSI-positive tumors showing low COX-2 expression.

Conclusions The number of TILs, which was increased by MSI and decreased by COX-2 expression, was associated with a poorer prognosis in patients with endometrial cancer. We also propose that COX-2 may block MSI-activated TILs in the tumor microenvironment.

  • CD8+ T lymphocytes
  • Cyclooxygenase 2
  • Endometrial cancer
  • Microsatellite instability

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Footnotes

  • This study was supported in part by grants from the Japan Ministry of Education, Culture, Sports, Science and Technology, Basic Research Foundation C (#22591867); Grants-in-Aid for Cancer Research and the Third Term Comprehensive Control Research for Cancer from the Japan Ministry of Health, Labor and Welfare (21bunshi-9-2); and the National Cancer Research and Development Fund (23-A-2).

  • The authors declare no conflicts of interest.

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