The prognostic significance of immune microenvironment in breast ductal carcinoma in situ

Abstract

Background The role of different subtypes of tumour infiltrating lymphocytes (TILs) in breast ductal carcinoma in situ (DCIS) is still poorly defined. This study aimed to assess the prognostic significance of B and T lymphocytes and immune checkpoint proteins expression in DCIS. Methods A well characterised DCIS cohort ( n = 700) with long-term follow-up comprising pure DCIS ( n = 508) and DCIS mixed with invasive carcinoma (IBC; n = 192) were stained immunohistochemically for CD20, CD3, CD4, CD8, FOXP3, PD1 and PDL1. Copy number variation and TP53 mutation status were assessed in a subset of cases ( n = 58). Results CD3+ lymphocytes were the predominant cell subtype in the pure DCIS cohort, while FOXP3 showed the lowest levels. PDL1 expression was mainly seen in the stromal TILs. Higher abundance of TILs subtypes was associated with higher tumour grade, hormone receptor negativity and HER2 positivity. Mutant TP53 variants were associated with higher levels of stromal CD3+, CD4+ and FOXP3+ cells. DCIS coexisting with invasive carcinoma harboured denser stromal infiltrates of all immune cells and checkpoint proteins apart from CD4+ cells. Stromal PD1 was the most differentially expressed protein between DCIS and invasive carcinoma ( Z = 5.8, p < 0.0001). Dense TILs, stromal FOXP3 and PDL1 were poor prognostic factors for DCIS recurrence, while dense TILs were independently associated with poor outcome for all recurrences (HR = 7.0; p = 0.024), and invasive recurrence (HR = 2.1; p = 0.029). Conclusions Immunosuppressive proteins are potential markers for high risk DCIS and disease progression. Different stromal and intratumoural lymphocyte composition between pure DCIS, DCIS associated with IBC and invasive carcinoma play a potential role in their prognostic significance and related to the underlying genomic instability. Assessment of overall TILs provides a promising tool for evaluation of the DCIS immune microenvironment.

Prognostic and predictive significance of tumor infiltrating lymphocytes for ductal carcinoma in situ

“…Different stromal lymphocyte composition between DCIS and IBC may be another answer for the potential different roles in their prognostic significance and relation with the underlying genomic instability. 35 Immunofluorescence analysis showed more activated CD8 + T cells in DCIS than in IBC whereas T cells of IBC samples were more similar to Tregs, suggesting a stronger immunosuppression in IBC compared with DCIS. 10 Modern immune researches have focused on the characteristics of different subtypes of TILs in DCIS and their relation with recurrence risk.…”

Tumour‐infiltrating lymphocytes in ductal carcinoma in situ (DCIS)—assessment with three different methodologies and correlation with Oncotype DX DCIS Score

“…15,16,[23][24][25][26] Toss et al characterised immune subtypes in 508 patients with pure DCIS and although they found that high expression levels of the immunosuppressive proteins stromal FOXP3 and PD-L1 were poor prognostic factors for recurrence, in multivariate analysis overall touching TIL density was the strongest independent predictor of DCIS recurrence. 27 They concluded that assessment of TILs on H&E-stained slides could provide the greatest prognostic data without the need for immune marker assessment. 27 In our study, patients with DCIS showing high nuclear grade and/or necrosis were significantly less likely to have a low ODX DCIS Score.…”

“…27 They concluded that assessment of TILs on H&E-stained slides could provide the greatest prognostic data without the need for immune marker assessment. 27 In our study, patients with DCIS showing high nuclear grade and/or necrosis were significantly less likely to have a low ODX DCIS Score. Furthermore, stromal TILs and touching TILs were associated with high nuclear grade, but circumferential TILs were not.…”

Immune Effective Score As A Predictor Of Response To Neoadjuvant Trastuzumab Therapy And A Prognostic Indicator For HER2-positive Breast Cancer

“…Evaluation of IES for the prognostic prediction of HER2-positive BC in TCGA cohort and METABRIC cohort From a variety of studies, it is now well established that immune functions play an important prognostic role in BC [21][22][23] . Thus, we sought to explore whether the IES as a predictor in HER2-positive BC has prognostic potential.…”