Targeting Transcriptional Regulators of CD8+ T Cell Dysfunction to Boost Anti-Tumor Immunity

Waugh, Katherine A.; Leach, Sonia M.; Slansky, Jill E.

doi:10.3390/vaccines3030771

Cited by 11 publications

(20 citation statements)

References 190 publications

(304 reference statements)

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“…We realised that nearly half of the differentially expressed genes were shared between CHB and HCC, indicating that the T cells dysfunction occurring in these two conditions were highly identical but still each has its own specific attributes. In agreement with what have been described in earlier publications,31 our results highlighted similar transcriptional trends in the exhausted CD8 +T cells including elevated expression of immune inhibitory receptors such as PD-1and CTLA-4 and distinctive expression pattern of many key transcriptional regulators such as FoxO1 and FoxO3 compared with that in control group.…”

Section: Discussionsupporting

confidence: 93%

T cell dysfunction in chronic hepatitis B infection and liver cancer: evidence from transcriptome analysis

et al. 2018

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BackgroundT cell dysfunction occurs in many diseases, especially in chronic virus infection and cancers. However, up to now, little is known on the distinctions in T cell exhaustion between cancer and chronic virus infection. The objective of this study is to explore the transcriptional similarities and differences in exhausted CD8 +T cell between chronic hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC).MethodsRNA sequencing was performed to compare the transcriptome of CD8 +T cells isolated from healthy donors’ blood, tumour tissues of patients with HCC and chronic HBV infected HCC patients’ paracancerous tissues. DESeq2 algorithm was used to determine differentially expressed genes. Gene ontology and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis was conducted for in-depth analysis of these differentially expressed genes.ResultsA total number of 2109 and 2203 genes were differentially expressed in patients with chronic HBV infection and HCC, respectively. Comparing these two groups of differentially deregulated genes, we found that nearly half of them were shared, and these shared genes were further classified into several functional categories, such as metabolic process, binding and intracellular organelle. KEGG analysis revealed that these shared deregulated genes were involved in many important pathways such as Parkinson’s disease, oxidative phosphorylation and messenger RNA surveillance. Interestingly, we reported that chronic HBV infection specific deregulated genes were mainly enriched in graft versus host disease, allograft rejection, phenylalanine, tyrosine and tryptophan biosynthesis pathways. Whereas, HCC-specific deregulated genes were highly enriched in oxidative phosphorylation, thyroid cancer and endometrial cancer pathways.ConclusionOur study demonstrated that T cell dysfunction associated with HCC and chronic HBV infection shares high similarities, however, each possesses its own features in terms of specific genes and signalling pathways. Uncovering the differences of T cells dysfunction would facilitate our understanding the diseases pathogenesis and developing innovative therapies in the future.

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Section: Discussionsupporting

confidence: 93%

T cell dysfunction in chronic hepatitis B infection and liver cancer: evidence from transcriptome analysis

et al. 2018

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“…To ultimately define the collective impact of multiple pathways suppressing CT26 TIL function (44), a comparison of genome-wide mRNA expression of tumor-specific CD8+ T cells from the tumor was required (Figure 2A). Tumor bearing mice were vaccinated to expand tumor-specific CD8+ T cells for detection in the periphery.…”

Section: Resultsmentioning

confidence: 99%

“…Both scenarios are in line with current literature; CD8+ T cell hypofunction varies by patient, assaulting malignancy, and over time (5, 48). A shift in focus towards overlapping mechanisms known to underlie multiple hypofunctional T cell subsets may enhance the functional response in the majority of heterogeneous TILN and TIL (44). …”

Section: Discussionmentioning

confidence: 99%

“…Transcriptional regulators interpret multiple extracellular signals to determine T cell function and differentiation; such intracellular targets represent promising avenues to simultaneously disrupt multiple inhibitory pathways that restrict anti-tumor function of TIL (44). FOXP1, a transcription factor that has recently been reported as highly expressed in TIL and a key regulator of T cell hypofunction in many cancers (78), is down-regulated in TASPR TIL from CT26 tumors.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model

Waugh

Leach

Moore

et al. 2016

The Journal of Immunology

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Mechanisms of self-tolerance often result in CD8+ tumor-infiltrating lymphocytes (TIL) with a hypofunctional phenotype incapable of tumor clearance. Using a transplantable colon carcinoma model, we found that CD8+ T cells became tolerized in less than 24 hours in an established tumor environment. To define the collective impact of pathways suppressing TIL function, we compared genome-wide mRNA expression of tumor-specific CD8+ T cells from the tumor and periphery. Notably, gene expression induced during TIL hypofunction more closely resembled self-tolerance than viral-exhaustion. Differential gene expression was refined to identify a core set of genes that defined hypofunctional TIL; these data comprise the first “molecular profile” of tumor-specific TIL that are naturally responding and represent a polyclonal repertoire. The molecular profile of TIL was further dissected to determine the extent of overlap and distinction between pathways that collectively restrict T cell functions. As suggested by the molecular profile of TIL, protein expression of inhibitory receptor LAG-3 was differentially regulated throughout prolonged late-G1/early-S phase of the cell cycle. Our data may accelerate efficient identification of combination therapies to boost anti-tumor function of TIL specifically against tumor cells.

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“…Isolation and cloning of T cells from primary tumors has difficulties stemming from issues such as T-cell exhaustion and anergy, as well as the deleterious environment of the tumor (28). We expected that isolation of T cells from the sentinel LN would provide a potential source of tumor-specific T cells, less affected by the tumor environment.…”

Section: Discussionmentioning

confidence: 99%

Identification of shared TCR sequences from T cells in human breast cancer using emulsion RT-PCR

Munson

Egelston

Chiotti

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Infiltration of T cells in breast tumors correlates with improved survival of patients with breast cancer, despite relatively few mutations in these tumors. To determine if T-cell specificity can be harnessed to augment immunotherapies of breast cancer, we sought to identify the alpha-beta paired T-cell receptors (TCRs) of tumor-infiltrating lymphocytes shared between multiple patients. Because TCRs function as heterodimeric proteins, we used an emulsion-based RT-PCR assay to link and amplify TCR pairs. Using this assay on engineered T-cell hybridomas, we observed ∼85% accurate pairing fidelity, although TCR recovery frequency varied. When we applied this technique to patient samples, we found that for any given TCR pair, the dominant alpha-or beta-binding partner comprised ∼90% of the total binding partners. Analysis of TCR sequences from primary tumors showed about fourfold more overlap in tumor-involved relative to tumor-free sentinel lymph nodes. Additionally, comparison of sequences from both tumors of a patient with bilateral breast cancer showed 10% overlap. Finally, we identified a panel of unique TCRs shared between patients' tumors and peripheral blood that were not found in the peripheral blood of controls. These TCRs encoded a range of V, J, and complementarity determining region 3 (CDR3) sequences on the alpha-chain, and displayed restricted V-beta use. The nucleotides encoding these shared TCR CDR3s varied, suggesting immune selection of this response. Harnessing these T cells may provide practical strategies to improve the shared antigen-specific response to breast cancer.T-cell receptors | breast cancer | emulsion RT-PCR | high-throughput sequencing | T-cell repertoire profiling I nfiltration of numerous tumors by CD8 + alpha-beta T cells is associated with better outcomes and longer survival times for patients with breast cancer (1-5). Targeted immune-based therapies hold great promise toward improving breast cancer treatments (6, 7). Studies have examined the immune phenotype of breast cancer tumor-infiltrating lymphocytes (TILs), suggesting that activated nonsuppressive T cells are of most benefit (8). Further assessment of the TIL repertoire has broad implications for breast cancer therapies in antigen discovery, cancer vaccines, and adoptive cell therapies (7).Unique genetic recombination events are required to produce the T-cell receptor (TCR) (reviewed in 9). The alpha-and beta-chains of the TCR undergo V(D)J recombination and heterodimerize in the thymus, resulting in a diverse T-cell repertoire that specifically recognizes peptide-MHC complexes. Many studies have analyzed the alpha-and beta-chains of TIL TCRs separately using highthroughput sequencing to describe the diversity of TILs (10-13). Pairs are readily identified after expansion of T-cell clones, although culture of T cells can lead to substantial skewing of the repertoire (14), which may select for T cells of varied affinity or avidity (15). Single-cell sequencing identifies alpha-beta pairs, but is often laborious and has rela...

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Targeting Transcriptional Regulators of CD8+ T Cell Dysfunction to Boost Anti-Tumor Immunity

Cited by 11 publications

References 190 publications

T cell dysfunction in chronic hepatitis B infection and liver cancer: evidence from transcriptome analysis

T cell dysfunction in chronic hepatitis B infection and liver cancer: evidence from transcriptome analysis

Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model

Identification of shared TCR sequences from T cells in human breast cancer using emulsion RT-PCR

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