Jenny-Maria Jönsson

Tertiary lymphoid structures in high-grade serous tubo-ovarian carcinoma: anatomical site matters

Abstract Tertiary lymphoid structures (TLS) in the tumor microenvironment are prognostically beneficial in many solid cancer types. Reports on TLS in high-grade serous tubo-ovarian carcinoma (HGSC) are few, and the prognostic impact is unclear. We investigated mature TLS (mTLS), immature TLS (iTLS) and lymphoid aggregates (LA) in primary adnexal tumors (PTs) and synchronous omental/peritoneal metastases (pMets) of HGSC. Whole H&E slides were scrutinized for mTLS and LA in a population-based cohort of 130 cases with stage III-IV HGSC. The immune cell tumor infiltration was evaluated with single chromogenic immunohistochemistry (IHC) on a tissue microarray (TMA) from the same cases. Selected whole slides (PT n = 11, pMet n = 10) of the cases most abundant in mTLS and LA were further investigated with multiplex IHC and immunofluorescence using digital image analysis (QuPath), to confirm TLS status and map the T and B lymphocyte subtypes. The results showed that mTLS were more common in pMets than in PTs but did not have an independent prognostic impact on overall or progression-free survival. The presence of mTLS correlated with intratumoral infiltration of CD8+ cytotoxic T cells, FOXP3+ regulatory T cells and PD-1+ lymphocytes in pMets only. Although overall mTLS cell composition was similar between PTs and pMets, the outer zones of mTLS in PTs were more immune cell-rich. In conclusion, our results indicate differences in TLS presence and cellular elements between primary adnexal tumors and synchronous peritoneal metastases, which are important to consider when conducting studies of the immune environment in HGSC.

MET Expression and Cancer Stem Cell Networks Impact Outcome in High-Grade Serous Ovarian Cancer

Overexpression of the receptor tyrosine kinase MET has been linked to poor survival in several cancer types, and MET has been suggested to interact with stem cell networks. In vitro studies have further suggested a possible benefit of a combined treatment using PARP and MET inhibitors. We used a tissue microarray (TMA) with 130 samples of advanced-stage high-grade serous fallopian tube/ovarian cancer (HGSC) to investigate the prognostic value of MET protein expression alone and in combination with the stem cell factor SOX2. The possible synergistic effects of a PARP and MET inhibitor treatment were evaluated in two cell lines with BRCA1 or BRCA2 deficiency and in their BRCA1/2-proficient counterparts. Patients with tumors positive for MET had worse overall survival (log-rank test, p = 0.015) compared to patients with MET-negative tumors. The prognostic role of MET was even more prominent in the subgroup of patients with SOX2-negative tumors (p = 0.0081). No synergistic effects of the combined treatment with PARP and MET inhibitors were found in the cell lines examined. We conclude that MET expression could be used as a marker for OS in HGSC and that stemness should be taken into consideration when evaluating the mechanisms of this effect.