Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates

Abstract

Various forms of immunotherapy, such as checkpoint blockade immunotherapy, are proving to be effective at restoring T cell-mediated immune responses that can lead to marked and sustained clinical responses, but only in some patients and cancer types. Patients and tumours may respond unpredictably to immunotherapy partly owing to heterogeneity of the immune composition and phenotypic profiles of tumour-infiltrating lymphocytes (TILs) within individual tumours and between patients. Although there is evidence that tumour-mutation-derived neoantigen-specific T cells play a role in tumour control, in most cases the antigen specificities of phenotypically diverse tumour-infiltrating T cells are largely unknown. Here we show that human lung and colorectal cancer CD8 TILs can not only be specific for tumour antigens (for example, neoantigens), but also recognize a wide range of epitopes unrelated to cancer (such as those from Epstein-Barr virus, human cytomegalovirus or influenza virus). We found that these bystander CD8 TILs have diverse phenotypes that overlap with tumour-specific cells, but lack CD39 expression. In colorectal and lung tumours, the absence of CD39 in CD8 TILs defines populations that lack hallmarks of chronic antigen stimulation at the tumour site, supporting their classification as bystanders. Expression of CD39 varied markedly between patients, with some patients having predominantly CD39 CD8 TILs. Furthermore, frequencies of CD39 expression among CD8 TILs correlated with several important clinical parameters, such as the mutation status of lung tumour epidermal growth factor receptors. Our results demonstrate that not all tumour-infiltrating T cells are specific for tumour antigens, and suggest that measuring CD39 expression could be a straightforward way to quantify or isolate bystander T cells.

Treatment-naïve HPV+ head and neck cancers display a T-cell-inflamed phenotype distinct from their HPV- counterparts that has implications for immunotherapy

“…CD39 was recently shown to be exclusively expressed on tumor antigen-specific CD8 + T-cells and not bystander CD8 + T-cells in colorectal and lung tumors. 33 Notably, CD39 showed significantly higher RNA expression levels in HPV+ HNSCC tumors compared to HPV- HNSCC samples (Figure 6). Interestingly, individual tumors expressing high levels of CD39 also co-expressed high levels of the four exhaustion markers (r values ranging from 0.37 to 0.62), suggesting that these genes are coordinately expressed (Supplementary Figure 5).…”

“…CD39 is an immunosuppressive molecule that can be expressed on intratumoral Tregs 32 and tumor-specific CD8 + TILs, but not bystander CD8 + T-cells. 33 CD39 RNA expression was higher in both HPV+ and HPV- HNSCC tumors compared to normal samples (Figure 6). Of note, CD39 expression in HPV+ HNSCC was significantly higher than HPV- tumors.…”

The expanding role of systems immunology in decoding the T cell receptor repertoire

“…Beyond immune receptor sequencing, there are other experimental technologies that are also advancing and provide potential opportunities for valuable insights and new perspectives. The ability to analyze large cell populations for tens to hundreds of protein parameters using mass cytometry [75], along with the advances in emulsion-based single cell RNA-sequencing that can be coupled with TCR sequencing [76], will likely establish high-dimensional single cell analysis as the basis of many immunological studies going forward.…”

Phenotype molding of T cells in colorectal cancer by single‐cell analysis

“…In line with our results, Simoni et al . showed that tumor‐infiltrating CD8+ CD28− T cells are abundant in CRC . Some studies demonstrated that these cells serve as the regulatory/suppressive subsets among the CD8+ T‐cell population .…”