Non-conventional inhibitory CD4(+)Foxp3(−)PD-1(hi) T cells as a biomarker of immune checkpoint blockade activity Journal Article
| Authors: | Zappasodi, R.; Budhu, S.; Hellmann, M. D.; Postow, M. A.; Senbabaoglu, Y.; Manne, S.; Gasmi, B.; Liu, C.; Zhong, H.; Li, Y.; Huang, A. C.; Hirschhorn-Cymerman, D.; Panageas, K. S.; Wherry, E. J.; Merghoub, T.; Wolchok, J. D. |
| Article Title: | Non-conventional inhibitory CD4(+)Foxp3(−)PD-1(hi) T cells as a biomarker of immune checkpoint blockade activity |
| Abstract: | A significant proportion of cancer patients do not respond to immune checkpoint blockade. To better understand the molecular mechanisms underlying these treatments, we explored the role of CD4+Foxp3− T cells expressing PD-1 (4PD1hi) and observed that 4PD1hi accumulate intratumorally as a function of tumor burden. Interestingly, CTLA-4 blockade promotes intratumoral and peripheral 4PD1hi increases in a dose-dependent manner, while combination with PD-1 blockade mitigates this effect and improves anti-tumor activity. We found that lack of effective 4PD1hi reduction after anti-PD-1 correlates with poor prognosis. Mechanistically, we provide evidence that mouse and human circulating and intra-tumor 4PD1hi inhibit T cell functions in a PD-1/PD-L1 dependent fashion and resemble follicular helper T cell (TFH)-like cells. Accordingly, anti-CTLA-4 activity is improved in TFH deficient mice. Zappasodi et al. show that a subset of CD4+Foxp3− T cells with high PD-1 expression, designated 4PD1hi cells, inhibits T cell functions. CTLA-4 blockade increases intratumoral and systemic 4PD1hi cells, while combination with PD-1 blockade reduces the increase of 4PD1hi cells and improves anti-tumor activity. © 2018 Elsevier Inc. |
| Keywords: | controlled study; human tissue; human cell; monotherapy; nonhuman; cd8+ t lymphocyte; cell proliferation; t lymphocyte; animal cell; mouse; phenotype; animal tissue; interleukin 2; ipilimumab; cancer immunotherapy; gene expression; in vivo study; lymphocyte differentiation; immune tolerance; gamma interferon; tissue distribution; upregulation; ctla-4; regulatory t cells; tumor necrosis factor; pd-1; non small cell lung cancer; metastatic melanoma; pd-l1; follicular helper t cells; cd4+ t cells; immune checkpoint blockade; b lymphocyte activation; immune resistance; nivolumab; human; priority journal; article; pembrolizumab; cd4 foxp3 pd 1 t cell |
| Journal Title: | Cancer Cell |
| Volume: | 33 |
| Issue: | 6 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2018-06-11 |
| Start Page: | 1017 |
| End Page: | 1032.e7 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2018.05.009 |
| PROVIDER: | scopus |
| PUBMED: | 29894689 |
| PMCID: | PMC6648657 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 July 2018 -- Source: Scopus |
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