The ratio of exhausted to resident infiltrating lymphocytes is prognostic for colorectal cancer patient outcome
Journal Title
Cancer Immunology Research
Publication Type
epub ahead of print
Abstract
Immunotherapy success in colorectal cancer (CRC) is mainly limited to patients whose tumors exhibit high microsatellite instability (MSI). However, there is variability in treatment outcomes within this group, which is in part driven by the frequency and characteristics of tumor infiltrating immune cells. Indeed, the presence of specific infiltrating immune-cell subsets has been shown to correlate with immunotherapy response and is in many cases prognostic of treatment outcome. Tumor-infiltrating lymphocytes (TILs) can undergo distinct differentiation programs, acquiring features of tissue-residency or exhaustion, a process during which T cells upregulate inhibitory receptors such as PD-1 and lose functionality. Although residency and exhaustion programs of CD8+ T cells are relatively well-studied, these programs have only recently been appreciated in CD4+ T cells and remain largely unknown in tumor-infiltrating natural killer (NK) cells. In this study, we used single-cell RNA sequencing (RNA-seq) data to identify signatures of residency and exhaustion in CRC infiltrating lymphocytes, including CD8+, CD4+ and NK cells. We then tested these signatures in independent single-cell data from tumor and normal tissue infiltrating immune cells. Further, we used versions of these signatures designed for bulk RNA-seq data to explore tumor intrinsic mutations associated with residency and exhaustion from TCGA data. Finally, using two independent transcriptomic data sets from patients with colon adenocarcinoma, we showed that combinations of these signatures, in particular combinations of NK-cell activity signatures, together with tumor-associated signatures, such as TGFβ signaling, were associated with distinct survival outcomes in patients with colon adenocarcinoma.
Publisher
AACR
WEHI Research Division(s)
Bioinformatics
PubMed ID
34413087
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2021-09-17 11:04:07
Last Modified: 2021-09-17 11:07:03
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