Moving forward to address key unanswered questions on targeting PD-1/PD-L1 in cancer: limitations in preclinical models and the need to incorporate human modifying factors
Abstract The tremendous clinical success of immune checkpoint inhibition (ICI), particularly targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1/2 (PD-L1/2) pathway, has resulted in application to multiple cancers, as a monotherapy and as a companion to both conventional a...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2019-11-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-019-0789-4 |
| _version_ | 1819114343418036224 |
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| author | Catherine T. Le William J. Murphy |
| author_facet | Catherine T. Le William J. Murphy |
| author_sort | Catherine T. Le |
| collection | DOAJ |
| description | Abstract The tremendous clinical success of immune checkpoint inhibition (ICI), particularly targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1/2 (PD-L1/2) pathway, has resulted in application to multiple cancers, as a monotherapy and as a companion to both conventional and novel agents. Despite this, the precise mechanisms underlying the anti-tumor effects of PD-1/PD-L1 blockade remain unclear. Emphasis has centered on its reversal of tumor-specific CD8+ T-cell exhaustion, although many cell types and processes are likely impacted. Due to the complex and pervasive roles of PD-1/PD-L1 on T-cell biology, including on initial T-cell priming, PD-1 blockade likely affects all aspects of T- cell responses, and these other effects may be even more critical for durable anti-tumor responses. Delineating these complex interactions necessitates in vivo modeling. By far, the healthy, young and inbred laboratory mouse, transplanted with an extensively cultured tumor cell line, has been the predominant preclinical model used to assess potential therapeutic efficacies. However, these mouse models often do not adequately reflect the tumor progression and cellular and genetic heterogeneity found within human cancers. Furthermore, laboratory mice also present with a vastly restricted immune profile compared to humans. This commentary discusses some of the critical questions that need to be addressed to optimize the use of ICI as well as caveats and limitations for consideration when extrapolating preclinical mouse data to the human cancer scenario. |
| first_indexed | 2024-12-22T04:43:47Z |
| format | Article |
| id | doaj.art-b256ebe432a74d7fa6d073e20ef2837b |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-22T04:43:47Z |
| publishDate | 2019-11-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-b256ebe432a74d7fa6d073e20ef2837b2022-12-21T18:38:39ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-11-01711510.1186/s40425-019-0789-4Moving forward to address key unanswered questions on targeting PD-1/PD-L1 in cancer: limitations in preclinical models and the need to incorporate human modifying factorsCatherine T. Le0William J. Murphy1Department of Dermatology, School of Medicine, University of California, DavisDepartment of Dermatology, School of Medicine, University of California, DavisAbstract The tremendous clinical success of immune checkpoint inhibition (ICI), particularly targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1/2 (PD-L1/2) pathway, has resulted in application to multiple cancers, as a monotherapy and as a companion to both conventional and novel agents. Despite this, the precise mechanisms underlying the anti-tumor effects of PD-1/PD-L1 blockade remain unclear. Emphasis has centered on its reversal of tumor-specific CD8+ T-cell exhaustion, although many cell types and processes are likely impacted. Due to the complex and pervasive roles of PD-1/PD-L1 on T-cell biology, including on initial T-cell priming, PD-1 blockade likely affects all aspects of T- cell responses, and these other effects may be even more critical for durable anti-tumor responses. Delineating these complex interactions necessitates in vivo modeling. By far, the healthy, young and inbred laboratory mouse, transplanted with an extensively cultured tumor cell line, has been the predominant preclinical model used to assess potential therapeutic efficacies. However, these mouse models often do not adequately reflect the tumor progression and cellular and genetic heterogeneity found within human cancers. Furthermore, laboratory mice also present with a vastly restricted immune profile compared to humans. This commentary discusses some of the critical questions that need to be addressed to optimize the use of ICI as well as caveats and limitations for consideration when extrapolating preclinical mouse data to the human cancer scenario.http://link.springer.com/article/10.1186/s40425-019-0789-4PD-1PD-L1ExhaustionPrimingT-cellPreclinical modeling |
| spellingShingle | Catherine T. Le William J. Murphy Moving forward to address key unanswered questions on targeting PD-1/PD-L1 in cancer: limitations in preclinical models and the need to incorporate human modifying factors Journal for ImmunoTherapy of Cancer PD-1 PD-L1 Exhaustion Priming T-cell Preclinical modeling |
| title | Moving forward to address key unanswered questions on targeting PD-1/PD-L1 in cancer: limitations in preclinical models and the need to incorporate human modifying factors |
| title_full | Moving forward to address key unanswered questions on targeting PD-1/PD-L1 in cancer: limitations in preclinical models and the need to incorporate human modifying factors |
| title_fullStr | Moving forward to address key unanswered questions on targeting PD-1/PD-L1 in cancer: limitations in preclinical models and the need to incorporate human modifying factors |
| title_full_unstemmed | Moving forward to address key unanswered questions on targeting PD-1/PD-L1 in cancer: limitations in preclinical models and the need to incorporate human modifying factors |
| title_short | Moving forward to address key unanswered questions on targeting PD-1/PD-L1 in cancer: limitations in preclinical models and the need to incorporate human modifying factors |
| title_sort | moving forward to address key unanswered questions on targeting pd 1 pd l1 in cancer limitations in preclinical models and the need to incorporate human modifying factors |
| topic | PD-1 PD-L1 Exhaustion Priming T-cell Preclinical modeling |
| url | http://link.springer.com/article/10.1186/s40425-019-0789-4 |
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