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. 2023 Apr 9;11(8):1073.
doi: 10.3390/healthcare11081073.

Promising Therapeutic Impact of Immune Checkpoint Inhibitors in Type II Endometrial Cancer Patients with Deficient Mismatch Repair Status

Kiyoka Sawada  1 , Kentaro Nakayama  1 , Sultana Razia  1 , Hitomi Yamashita  1 , Tomoka Ishibashi  1 , Masako Ishikawa  1 , Kosuke Kanno  1 , Seiya Sato  1 , Satoru Nakayama  2 , Yoshiro Otsuki  3 , Satoru Kyo  1
Affiliations

Promising Therapeutic Impact of Immune Checkpoint Inhibitors in Type II Endometrial Cancer Patients with Deficient Mismatch Repair Status

Kiyoka Sawada et al. Healthcare (Basel). .

Abstract

Type II endometrial cancer (EC) is responsible for most endometrial cancer-related deaths due to its aggressive nature, late-stage detection, and high tolerance to standard therapies. Thus, novel treatment strategies for type II EC are imperative. For patients with mismatch repair-deficient (dMMR) tumors, immunotherapy with immune checkpoint inhibitors represents a promising therapeutic strategy. However, the prevalence of dMMR tumors in type II EC patients remains unclear. In this study, using immunohistochemistry, we evaluated the expression of mismatch repair (MMR) proteins, tumor-infiltrating lymphocytes (CD8+), and immune checkpoint molecules (PD-L1) in 60 patients with type II EC (16, 5, 17, and 22 were endometrioid G3, serous, de-differentiated, and carcinosarcoma cases, respectively) to investigate the therapeutic effect of immune checkpoint inhibitors. Approximately 24 cases (40%) had a loss of MMR protein expression. The positivity rate of CD8+ (p = 0.0072) and PD-L1 (p = 0.0061) expression was significantly associated with the dMMR group. These results suggest immune checkpoint inhibitors (anti-PD-L1/PD-1 antibodies) could effectively treat type II EC with dMMR. The presence of dMMR might be a biomarker for a positive response to PD-1/PD-L1 immunotherapy in type II EC.

Keywords: deficient mismatch repair system; endometrial cancer; immune checkpoint inhibitors; type II.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Representative images of immunostaining of MMR proteins in type II EC. (A) There is no expression of MLH1. (B) There is positive expression of MLH1. (C) There is no expression of MSH2. (D) There is positive expression of MSH2. (E) There is no expression of MSH6. (F) There is positive expression of MSH6. (G) There is no expression of PMS2. (H) There is positive expression of PMS2.
Figure 1
Figure 1
Representative images of immunostaining of MMR proteins in type II EC. (A) There is no expression of MLH1. (B) There is positive expression of MLH1. (C) There is no expression of MSH2. (D) There is positive expression of MSH2. (E) There is no expression of MSH6. (F) There is positive expression of MSH6. (G) There is no expression of PMS2. (H) There is positive expression of PMS2.
Figure 2
Figure 2
(A,B) Representative images of CD8 staining in type II EC. (A) Negative expression of CD8 (score 0). (B) Positive expression of CD8 (score 3+). (C,D) Representative images of PD-L1 staining in type II EC. (C) Negative expression of PD-L1. (D) Positive expression of PD-L1.
Figure 3
Figure 3
Prognostic analysis using Kaplan-Meier curves. (A) PFS (left panel) and (B) OS (right panel) analysis of type II EC patients between dMMR and pMMR group combining all stages together. (C) PFS (left panel) and (D) OS (right panel) analysis of type II EC patients between dMMR and pMMR groups for stage III/IV cases. (E) PFS (left panel) and (F) OS (right panel) analysis of type II EC patients between dMMR and pMMR groups for stage I/II cases. (G) PFS (left panel) and (H) OS (right panel) of type II EC patients with and without CD8 expression combining all stages together. (I) PFS (left panel) and (J) OS (right panel) of type II EC patients with and without PD-L1 expression combining all stages together.
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