Clinical implications of T cell exhaustion for cancer immunotherapy Review
| Authors: | Chow, A.; Perica, K.; Klebanoff, C. A.; Wolchok, J. D. |
| Review Title: | Clinical implications of T cell exhaustion for cancer immunotherapy |
| Abstract: | Immunotherapy has been a remarkable clinical advancement in the treatment of cancer. T cells are pivotal to the efficacy of current cancer immunotherapies, including immune-checkpoint inhibitors and adoptive cell therapies. However, cancer is associated with T cell exhaustion, a hypofunctional state characterized by progressive loss of T cell effector functions and self-renewal capacity. The ‘un-exhausting’ of T cells in the tumour microenvironment is commonly regarded as a key mechanism of action for immune-checkpoint inhibitors, and T cell exhaustion is considered a pathway of resistance for cellular immunotherapies. Several elegant studies have provided important insights into the transcriptional and epigenetic programmes that govern T cell exhaustion. In this Review, we highlight recent discoveries related to the immunobiology of T cell exhaustion that offer a more nuanced perspective beyond this hypofunctional state being entirely undesirable. We review evidence that T cell exhaustion might be as much a reflection as it is the cause of poor tumour control. Furthermore, we hypothesize that, in certain contexts of chronic antigen stimulation, interruption of the exhaustion programme might impair T cell persistence. Therefore, the prioritization of interventions that mitigate the development of T cell exhaustion, including orthogonal cytoreduction therapies and novel cellular engineering strategies, might ultimately confer superior clinical outcomes and the greatest advances in cancer immunotherapy. © 2022, Springer Nature Limited. |
| Keywords: | signal transduction; cancer chemotherapy; protein expression; review; nonhuman; cancer radiotherapy; neoplasm; neoplasms; ki 67 antigen; cd8+ t lymphocyte; lymphocyte proliferation; t lymphocyte; t-lymphocytes; interleukin 2; tumor volume; in vivo study; cytotoxicity; b lymphocyte induced maturation protein 1; t lymphocyte receptor; immunotherapy; gamma interferon; cell culture; epigenetics; cd4+ t lymphocyte; cytotoxic t lymphocyte antigen 4; gamma interferon inducible protein 10; glucocorticoid induced tumor necrosis factor receptor; adoptive immunotherapy; immunotherapy, adoptive; cd19 antigen; cd28 antigen; transcription factor 7; programmed death 1 ligand 1; programmed death 1 receptor; cxcl9 chemokine; tumor microenvironment; nuclear receptor nur77; rantes; nuclear receptor related factor 1; chemokine receptor cxcr5; glycoprotein p 15095; peroxisome proliferator activated receptor gamma coactivator 1alpha; pi3k/akt signaling; cell engineering; humans; human; immune checkpoint inhibitors; cxcl13 chemokine; gene editing; crispr-cas9 system; hepatitis a virus cellular receptor 2; chimeric antigen receptor t-cell immunotherapy; tumor necrosis factor receptor superfamily member 9; single cell rna seq; cd39 antigen; nuclear receptor nr4a3 |
| Journal Title: | Nature Reviews Clinical Oncology |
| Volume: | 19 |
| Issue: | 12 |
| ISSN: | 1759-4774 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2022-12-01 |
| Start Page: | 775 |
| End Page: | 790 |
| Language: | English |
| DOI: | 10.1038/s41571-022-00689-z |
| PUBMED: | 36216928 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Review -- Export Date: 1 December 2022 -- Source: Scopus |
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