Targeted degradation of immune checkpoint proteins: emerging strategies for cancer immunotherapy

doi:10.1038/s41388-020-01491-w

Review

. 2020 Nov;39(48):7106-7113.

doi: 10.1038/s41388-020-01491-w. Epub 2020 Oct 6.

Targeted degradation of immune checkpoint proteins: emerging strategies for cancer immunotherapy

Jie Xu¹, Jean-Philippe Brosseau^{2

3}, Hubing Shi⁴

Affiliations

¹ Institutes of Biomedical Sciences and Zhongshan-Xuhui Hospital, Key Laboratory of Epigenetics and Metabolism, Fudan University, Shanghai, China. jie_xu@fudan.edu.cn.
² Centre de Recherche du Centre Hospitalier de Sherbrooke, Sherbrooke, Canada.
³ Department of Biochemistry and Functional Genomics, Université de Sherbrooke, Sherbrooke, Canada.
⁴ Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.

PMID: 33024277
DOI: 10.1038/s41388-020-01491-w

Review

Targeted degradation of immune checkpoint proteins: emerging strategies for cancer immunotherapy

Jie Xu et al. Oncogene. 2020 Nov.

. 2020 Nov;39(48):7106-7113.

doi: 10.1038/s41388-020-01491-w. Epub 2020 Oct 6.

Authors

Jie Xu¹, Jean-Philippe Brosseau^{2

3}, Hubing Shi⁴

Affiliations

¹ Institutes of Biomedical Sciences and Zhongshan-Xuhui Hospital, Key Laboratory of Epigenetics and Metabolism, Fudan University, Shanghai, China. jie_xu@fudan.edu.cn.
² Centre de Recherche du Centre Hospitalier de Sherbrooke, Sherbrooke, Canada.
³ Department of Biochemistry and Functional Genomics, Université de Sherbrooke, Sherbrooke, Canada.
⁴ Laboratory of Tumor Targeted and Immune Therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.

PMID: 33024277
DOI: 10.1038/s41388-020-01491-w

Abstract

Cancer immunotherapy using immune-checkpoint blockade has displayed promising clinical effects, but prevalent antibody-based inhibitors face multiple challenges such as low response rate, acquired resistance, and adverse effects. The intracellular expression of PD-1/PD-L1 in recycling endosomes and their active trafficking to membrane highlight the importance of depleting rather than interfering with checkpoint proteins. Preclinical investigations on the therapeutic effects of lead compounds that function by degrading immune checkpoint ligands and receptors have reported highly promising results. By harnessing the degradation capabilities of the lysosome, proteasome and autophagosomes, different small molecules and peptides potently induced degradation of checkpoint proteins and enhanced anti-tumor immunity. Both in vitro and in vivo experiments support the therapeutic efficacy of these molecules. Thus, targeted degradation through endo-lysosomal, autophagic, proteasomal, or endoplasmic reticulum-related pathways may provide promising strategies for tackling the challenges in cancer immunotherapy.

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References

1. Cha JH, Chan LC, Song MS, Hung MC. New approaches on cancer immunotherapy. Cold Spring Harbor perspectives in medicine. 2019;10:a036863.
1. Wang J, Sun J, Liu LN, Flies DB, Nie X, Toki M, et al. Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy. Nat Med. 2019;25:656–66. - PubMed - PMC
1. Hakenberg OW. Nivolumab for the treatment of bladder cancer. Expert Opin Biol Ther. 2017;17:1309–15. - PubMed
1. Greillier L, Tomasini P, Barlesi F. The clinical utility of tumor mutational burden in non-small cell lung cancer. Transl Lung Cancer Res. 2018;7:639–46. - PubMed - PMC
1. Esfahani K, Buhlaiga N, Thebault P, Lapointe R, Johnson NA, Miller WH Jr. Alemtuzumab for Immune-Related Myocarditis Due to PD-1 Therapy. N Engl J Med. 2019;380:2375–6. - PubMed

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[1] Cha JH, Chan LC, Song MS, Hung MC. New approaches on cancer immunotherapy. Cold Spring Harbor perspectives in medicine. 2019;10:a036863.

[2] Cha JH, Chan LC, Song MS, Hung MC. New approaches on cancer immunotherapy. Cold Spring Harbor perspectives in medicine. 2019;10:a036863.

[3] Wang J, Sun J, Liu LN, Flies DB, Nie X, Toki M, et al. Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy. Nat Med. 2019;25:656–66. - PubMed - PMC

[4] Wang J, Sun J, Liu LN, Flies DB, Nie X, Toki M, et al. Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy. Nat Med. 2019;25:656–66. - PubMed - PMC

[5] Hakenberg OW. Nivolumab for the treatment of bladder cancer. Expert Opin Biol Ther. 2017;17:1309–15. - PubMed

[6] Hakenberg OW. Nivolumab for the treatment of bladder cancer. Expert Opin Biol Ther. 2017;17:1309–15. - PubMed

[7] Greillier L, Tomasini P, Barlesi F. The clinical utility of tumor mutational burden in non-small cell lung cancer. Transl Lung Cancer Res. 2018;7:639–46. - PubMed - PMC

[8] Greillier L, Tomasini P, Barlesi F. The clinical utility of tumor mutational burden in non-small cell lung cancer. Transl Lung Cancer Res. 2018;7:639–46. - PubMed - PMC

[9] Esfahani K, Buhlaiga N, Thebault P, Lapointe R, Johnson NA, Miller WH Jr. Alemtuzumab for Immune-Related Myocarditis Due to PD-1 Therapy. N Engl J Med. 2019;380:2375–6. - PubMed

[10] Esfahani K, Buhlaiga N, Thebault P, Lapointe R, Johnson NA, Miller WH Jr. Alemtuzumab for Immune-Related Myocarditis Due to PD-1 Therapy. N Engl J Med. 2019;380:2375–6. - PubMed

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Targeted degradation of immune checkpoint proteins: emerging strategies for cancer immunotherapy

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Targeted degradation of immune checkpoint proteins: emerging strategies for cancer immunotherapy

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