Tesis

Analisis Tumor-Infiltrating Lymphocytes (TILs) Sebagai Prediktor Derajat Keganasan Pada Kanker Ovarium = Tumor-Infiltrating Lymphocytes (TILs) Analysis as Predictor of Tumor Grade in Ovarian Cancer.

Latar Belakang Kanker ovarium tipe epitelial menyumbang lebih dari 70% kasus kanker ovarium, dengan proporsi derajat keganasan tinggi lebih banyak dibandingkan derajat keganasan rendahsedang. Imunogenisitas tumor, khususnya peran tumor-infiltrating lymphocytes (TILs) seperti sel T regulator (Treg) dan sel T sitotoksik CD8+ (CTL), dapat memberikan informasi penting sebagai prediktor klasifikasi derajat keganasan yang berkontribusi terhadap prognosis. Metode Profil imunogenik dianalisis menggunakan pemeriksaan flow cytometry terhadap penanda permukaan sel Treg (CD4+CD25+CD127-), CTL (CD8+), dan sitokin IFN- g intraseluler CD8+ pada sampel jaringan segar-beku kanker ovarium tipe epitelial yang telah dikelompokkan menjadi kelompok kanker ovarium tipe epitelial derajat keganasan rendah-sedang dan derajat keganasan tinggi. Analisis statistik dilakukan untuk menentukan hubungan antara setiap parameter. HasiProporsi Treg dan CTL meningkat pada kelompok derajat keganasan tinggi dibandingkan kelompok derajat keganasan rendah-sedang (0.361 ± 0.411 vs 0.946 ± 0.295, p = 0.000; dan -0.117 ± 0.671 vs 0.354 ± 0.411, p = 0.011). Ekspresi IFN- g pada CTL lebih tinggi ditemukan pada derajat keganasan tinggi (342 ± 67.916 vs 431.88 ± 105.358, p = 0.003), namun proporsi CTL yang mengekspresikan IFN- g tidak berbeda bermakna. Sebaliknya, rasio CTL teraktivasi lebih tinggi pada derajat rendah-sedang (1.971 ± 0.661 vs 1.418 ± 0.380, p = 0.004). Nilai cut-off Treg > 5.105% memiliki sensitivitas sebesar 81.3% dan spesifisitas 75% dalam membedakan derajat keganasan kanker ovarium tipe epitelial. Sementara nilai CTL > 0.89% menunjukkan sensitivitas 87.5% dan spesifisitas 68.7%. Kesimpulan Kombinasi proporsi Treg dan CTL yang tinggi, namun tidak disertai peningkatan aktivasi fungsional CTL, berhubungan dengan kanker ovarium derajat keganasan tinggi. Hal ini mencerminkan kondisi TME imunogenik sekaligus imunosupresif pada derajat keganasan tinggi. Nilai cut-off Treg 5.105% dan CTL 0.89% pada penelitian ini berpotensi menjadi prediktor derajat keganasan pada kanker ovarium.
Kata Kunci: karsinoma ovarium, derajat keganasan, Treg, CTL, interferon gamma


Introduction Epithelial ovarian cancer comprises both low-grade tumors with slower progression and high-grade tumors that are more aggressive and often diagnosed at advanced stages. The tumor’s immunogenicity, reflected by the presence of lymphocytes (TILs) such as regulatory T cells (Treg) and cytotoxic CD8+ T cells (CTL), may provide valuable information as potential predictor for grading classification that contributes to prognosis. MethoSamples were classified into two different groups based on their malignancy grade: lowto-moderate and high grade. Immunogenic profile of ovarian cancer was assessed by flow cytometry analysis to detect Treg and CTL based on their surface marker expression, as well as intracellular IFN- g in CD8+ on fresh-frozen epithelial ovarian cancer tissue samples. Statistical analysis was conducted to determine relation between each parameter. Results Significantly higher proportions of Tregs and CTLs were observed in high-grade group (0.361 ± 0.411 vs 0.946 ± 0.295, p = 0.000; and -0.117 ± 0.671 vs 0.354 ± 0.411, p = 0.011, respectively). IFN-γ expression in CTLs was also elevated in high-grade group (342 ± 67.916 vs 431.88 ± 105.358, p = 0.003); however, the proportion of CTLs expressing IFN-γ showed no significant difference between groups. Notably, the ratio of activated CTLs was significantly higher in the low-to-moderate grade group (1.971 ± 0.661 vs 1.418 ± 0.380, p = 0.004). Treg cut-off value > 5.105% demonstrated a sensitivity of 81.3% and a specificity of 75% in distinguishing the histological grade of epithelial ovarian cancer. In contrast, CTL cut-off value > 0.89% showed a sensitivity of 87.5% and a specificity of 68.7%. Conclusion A combination of high Treg and CTL proportions is associated with high-grade ovarian cancer. However, elevated CTL proportions are not accompanied by optimal functional activation, suggesting an immunogenic and immunosuppressive TME in higher-grade tumors, simultaneously. Treg and CTL cut-off values found in this study could help determine tumor grade in ovarian cancer.
Keywords: ovarian carcinoma, tumor grade, Treg, CTL, interferon gamma