Clonality, antigen recognition and suppression of CD8+ T cells differentially affect prognosis of breast cancer subtypes

Purpose: In breast cancer (BC), 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 datasets including 867 node-negative, treatment-naive BC patients (micro-array data) and 347 BC patients (whole-genome sequence and transcriptome data) according to parameters of T cells as well as immune micro-environment in relation to patient survival. Results: We developed a 109 immune-gene signature that captures abundance of CD8 TILs and is prognostic in basal-like, her2 and luminal-B BC, but not in luminal-A nor normal-like BC. Basal-like and her2 are characterized by highest CD8 TIL abundance, highest T cell clonality, highest frequencies of memory T cells, 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, co-inhibition and antigen presentation reflect occurrence of a CD8 T cell response in BC subtypes, which have been aborted by distinct T cell suppressive mechanisms, providing a rational for subtype-specific combination immune therapies.