Clonality, antigen recognition, and suppression of CD8+ T cells differentially affect prognosis of breast cancer subtypes
Purpose: In breast cancer, response rates to immune therapies are generally low and differ significantly across molecular subtypes, urging a better understanding of immunogenicity and immune evasion. Experimental Design: We interrogated large gene-expression data sets including 867 node-negative, treatment-naïve breast cancer patients (microarray data) and 347 breast cancer patients (whole-genome sequencing and transcriptome data) according to parameters of T cells as well as immune microenvironment in relation to patient survival. Results: We developed a 109-immune gene signature that captures abundance of CD8 tumor-infiltrating lymphocytes (TIL) and is prognostic in basal-like, her2, and luminal B breast cancer, but not in luminal A or normal-like breast cancer. Basal-like and her2 are characterized by highest CD8 TIL abundance, highest T-cell clonality, highest frequencies of memory T cells, and highest antigenicity, yet only the former shows highest expression level of immune and metabolic checkpoints and highest frequency of myeloid suppressor cells. Also, luminal B shows a high antigenicity and T-cell clonality, yet a low abundance of CD8 TILs. In contrast, luminal A and normal-like both show a low antigenicity, and notably, a low and high abundance of CD8 TILs, respectively, which associates with T-cell influx parameters, such as expression of adhesion molecules. Conclusions: Collectively, our data argue that not only CD8 T-cell presence itself, but rather T-cell clonality, T-cell subset distribution, coinhibition, and antigen presentation reflect occurrence of a CD8 T-cell response in breast cancer subtypes, which have been aborted by distinct T-cell-suppressive mechanisms, providing a rationale for subtype-specific combination immune therapies.
|Persistent URL||dx.doi.org/10.1158/1078-0432.CCR-19-0285, hdl.handle.net/1765/123956|
|Journal||Clinical Cancer Research|
Hammerl, D. (Dora), Massink, M.P.G, Smid, M. (Marcel), van Deurzen, C.H.M, Meijers-Heijboer, E.J, Waisfisz, Q. (Quinten), … Martens, J.W.M. (John W.M.). (2020). Clonality, antigen recognition, and suppression of CD8+ T cells differentially affect prognosis of breast cancer subtypes. Clinical Cancer Research, 26(2), 505–517. doi:10.1158/1078-0432.CCR-19-0285