Immune microenvironment in high-grade serous ovarian carcinomas: association with molecular profiles and neoadjuvant therapy outcome

Abstract

Introduction. The effect of chemotherapy is not limited to direct interaction between a given drug and tumor cells. In fact, cytostatic drugs induce a wide range of changes in the tumor immune microenvironment.

Aim. The research aims to analyze the expression profile of genes involved in immune regulation and inflammatory response; to evaluate the extent of inflammatory infiltration in high-grade serous ovarian carcinomas after the standard platinum-containing neoadjuvant chemotherapy; and to compare the results of molecular and morphological analysis with the clinical response to the treatment.

Materials and methods. The study involved 36 female patients who received a standard combination of paclitaxel and carboplatin as preoperative therapy. RNA from 25 primary tumor samples collected before the chemotherapy and from 28 postoperative residual tissues taken after the completion of neoadjuvant treatment were analyzed. The analysis was performed using the Human Inflammation and Immunity Transcriptome QIAseq Targeted RNA Panel (Qiagen, USA). In addition, lymphocytic infiltration was evaluated using the four-tier system (0 – no infiltration, 1 – minimal infiltration, 2 – focal occurrence, 3 – wide-spread occurrence). TP53 mutation types and levels of immune infiltration were compared in 107 primary and residual carcinomas. TP53 mutations were analyzed by the next-generation sequencing. 38 primary ovarian carcinomas were subjected to targeted DNA sequencing using the SeqCap EZ CNV/LOH Backbone Design panel. It allowed to analyze copy number alterations and build up chromosome instability profiles.

Results. The extent of lymphocytic infiltration observed before or after chemotherapy did not correlate with clinical response to paclitaxel and carboplatin therapy. CD3E, CXCL13, LYZ, CCL5, CD27, CD3D, IL2RG, CD2 and SELL genes were upregulated in chemonaive tumors with high content of lymphocytes. Increased expression of CCL18, CXCL13, CD27, LYZ, RUNX3 and SELL genes was observed in postsurgical tumor tissues with high lymphocyte infiltration. The frequency of increased lymphocyte infiltration was higher in chemonaive tumors with TP53 missense mutations compared to lesions with non-missense alterations. TP53 mutations had a stronger impact on the extent of infiltration in the context of chromosomal instability. All carcinomas with non-BRCAness profile and non-missense mutations had no or low infiltration (p = 0.03).

Conclusion. Targeted mRNA profiling of immune/inflammation-related genes allows identify carcinomas with high and low lymphocytic infiltration. The results of the study indicate a possible role of p53 in the tumor immune microenvironment.