Abstract PD5-11: Differential prognostic value of TILs in BC subtypes is attributed to antigen load and T cell suppression
Authors: Hammerl D , Massink MP , Smid M , van Deurzen C , Waisfisz Q , Meijers-Heijboer H , Debets R , Martens JW 
Published: May 2019

Abstract
In breast cancer (BC), tumor infiltrating lymphocytes (TILs), in particular CD8 T cells, have prognostic value, yet response rates to immune therapies are generally low and differ significantly across subtypes.
To define immune markers that would facilitate the identification of patient subgroups which respond to immune therapies, we assessed the quality and quantity of T cell evasive mechanisms in BC subtypes, using large gene expression datasets (microarray GSE2034/5327 and DNA/RNAseq: EGAS00001001178). To this end, we generated a 152 immune-gene signature, based on quantitative measurements of TILs. This TIL signature highly correlated with numbers of TCR reads (MIXCR, r=0.91, p&lt;0.0001) and frequencies of activated lymphocytes (Cibersort, such as CD8 T cells, follicular helper CD4 T cells and plasma cells), whereas this signature inversely correlated with frequencies of immune suppressor cells (such as M2 macrophages, MDSCs and neutrophils). We tested this signature for its prognostic value in our cohort of 344 LNN patients, not adjuvantly treated with hormone- or chemotherapy (GSE2034/5327). Luminal A and B subtypes had low average TIL scores. Her2 and basal-like tumors had equally high TIL scores, yet an association between TIL score and survival was only observed in the Her2 molecular subtype (HR=0.24, p&lt;0.001). Multi-immune parameter analysis demonstrated that Her2 BC is characterized by a high antigen load (extent of neo and cancer germline antigens) and relatively low frequencies of suppressor cells. In contrast, basal-like BC is characterized by the highest antigen load (p=0.003), the highest number of clonally expanded T cells (p&lt;0.001), the highest frequency of immune suppressor cells (p&lt;0.001), and significantly enhanced expression of co-inhibitory molecules (such as LAG3 and PD-L1). Notably, a subset of basal-like tumors had mutations in antigen presentation/processing pathways and/or lacked gene-expression of molecules involved in this pathway, suggesting selection of lesser immunogenic tumor cells. Interestingly, regardless of low antigen load, also normal-like BC had a high TIL score, yet no clonally expanded T cell clones, which suggests lack of a tumor-specific T cell response.
Collectively, these data suggest that not TIL score per se but rather the extent of immunogenicity and T cell suppressive mechanisms discriminate BC subtypes. These results point toward the requirement of different combinatorial approaches to boost the efficacy of immune therapies across BC subtypes.
Citation Format: Hammerl D, Massink MP, Smid M, van Deurzen C, Waisfisz Q, Meijers-Heijboer H, Debets R, Martens JW. Differential prognostic value of TILs in BC subtypes is attributed to antigen load and T cell suppression [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD5-11.