Correlation Between IFNγ+ and CTLA-4+ Tumor Infiltrating Lymphocytes In Luminal And Non-Luminal Breast Carcinoma

Irene Lingkan Parengkuan, Sjahjenny Mustokoweni, Nila Kurniasari



The role of tumor infiltrating lymphocytes (TIL) in breast carcinoma depends on the molecular subtype, especially the expression of the estrogen receptor. A greater mutation load in the non-luminal subtype leads to continuous activation of the immune system resulting in exhausted T lymphocytes. Observational research with a cross-sectional approach was conducted on 40 formalin fixed paraffin-embedded tissue from breast carcinoma at the Anatomical Pathology Laboratory of Dr. Soetomo General Hospital Surabaya during January 2017 -  December 2018. Samples were divided into two groups based on their status of ER expression. The parameter was a positive percentage of TIL immunoreactivity against IFNγ and CTLA-4 antibodies. Percentage of IFNγ+ TIL is higher in the luminal subtype (p =0.001), whereas the percentage of CTLA-4+ TIL is higher in the non-luminal (p =0.001). These expressions were significantly correlated with the molecular subtype of breast carcinoma (p=0.001). A significant correlation between IFNγ+ and CTLA-4+ TIL were found (rs=-0.350, p=0.027). Exhausted T lymphocytes express some inhibitor molecules such as CTLA-4. CTLA-4 (Cytotoxic T-Cell Lymphocyte Associated Protein-4) suppresses immune system function including the activity of IFN-γ as an important molecule in anti-tumor immunity and forms an immunosuppressive and pro-tumor microenvironment. Different level of expressions of IFNγ+ (p=0.001) and CTLA-4 + (p=0.001) TIL were proven to be related to the molecular subtype of breast carcinoma (rs=-0.683, p=0.001; rs=0,501, p=0.001, respectively). The negative correlation between IFNγ+ and CTLA-4+ TIL shows the role of CTLA-4 as an inhibitory molecule to the immune system (rs=-0.350, p=0.027).

Keywords : tumour infiltrating lymphocytes, IFNγ, CTLA-4, breast carcinoma,  luminal molecular subtype

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Peran tumour infiltrating lymphocytes (TIL) pada karsinoma payudara berhubungan erat dengan subtipe molekuler, terutama ada atau tidaknya ekspresi reseptor estrogen. Beban mutasi yang besar pada subtipe non-luminal menyebabkan pengaktifan sistem imun terjadi terus menerus dengan hasil akhir terbentuknya subset limfosit T yang kelelahan. Penelitian observasional analitik dengan pendekatan potong lintang ini menggunakan sampel 40 blok parafin dari penderita karsinoma payudara di Laboratorium Patologi Anatomi RSUD Dr. Soetomo Surabaya periode 1 Januari 2017 – 31 Desember 2018 yang dibagi menjadi 2 kelompok berdasarkan ada atau tidaknya ekspresi reseptor estrogen. Parameter penilaian adalah jumlah persentase TIL area tumor invasif yang terpulas positif dengan antibodi IFNγ dan CTLA-4. Ekspresi IFNγ+ TIL didapatkan lebih tinggi pada subtipe luminal (p=0,001), sedangkan ekspresi CTLA-4+ TIL didapatkan lebih tinggi pada subtipe non-luminal (p=0,001). Analisis statistik menunjukkan adanya korelasi signifikan antara ekspresi IFNγ+ TIL dengan CTLA-4+ TIL (rs=-0,350, p=0,027). Salah satu sifat dari sel limfosit T kelelahan adalah mengekspresikan molekul inhibitor sistem imun antara lain CTLA-4 (Cytotoxic T-Cell Lymphocyte Associated Protein-4). CTLA-4 akan menekan fungsi sistem imun dan berdampak pada penurunan aktivitas IFN-γ yang merupakan salah satu molekul penting dalam imunitas anti-tumor sehingga terbentuklah lingkungan mikro yang imunosupresif dan pro-tumor. Hasil penelitian menunjukkan adanya perbedaan ekspresi IFNγ+ TIL (p=0,001) dan CTLA-4+ TIL (p=0,001) pada kedua kelompok yang secara bermakna berhubungan dengan subtipe molekuler karsinoma payudara (secara berurutan mendapatkan nilai (rs=-0,683, p=0,001 dan rs=0,501, p=0,001). Korelasi negatif antara IFNγ+ TIL dengan CTLA-4+ TIL menunjukkan adanya peran CTLA-4 sebagai molekul inhibisi terhadap sistem imun (rs=-0,350, p=0,027).

Kata kunci                  : tumour infiltrating lymphocytes, IFNγ, CTLA-4, karsinoma payudara, subtipe molekuler luminal



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