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CTLA-4 blockade boosts the expansion of tumor-reactive CD8+ tumor-infiltrating lymphocytes in ovarian cancer

Friese, Christina ; Harbst, Katja LU orcid ; Borch, Troels Holz ; Westergaard, Marie Christine Wulff ; Pedersen, Magnus ; Kverneland, Anders ; Jönsson, Göran LU ; Donia, Marco ; Svane, Inge Marie and Met, Özcan (2020) In Scientific Reports 10(1).
Abstract

Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) can induce durable complete tumor regression in patients with advanced melanoma. Efforts are currently underway to expand this treatment modality to other cancer types. In the microenvironment of ovarian cancer, the engagement of co-inhibitory immune checkpoint molecules such as CTLA-4 can lead to the inactivation of TILs. Thus, approaches that directly manipulate co-inhibitory pathways within the tumor microenvironment might improve the expansion of tumor-reactive TILs. The initial expansion of TILs for ACT from tumor fragments provides a window of opportunity to manipulate an intact tumor microenvironment and improve CD8+ T-cell output and TIL... (More)

Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) can induce durable complete tumor regression in patients with advanced melanoma. Efforts are currently underway to expand this treatment modality to other cancer types. In the microenvironment of ovarian cancer, the engagement of co-inhibitory immune checkpoint molecules such as CTLA-4 can lead to the inactivation of TILs. Thus, approaches that directly manipulate co-inhibitory pathways within the tumor microenvironment might improve the expansion of tumor-reactive TILs. The initial expansion of TILs for ACT from tumor fragments provides a window of opportunity to manipulate an intact tumor microenvironment and improve CD8+ T-cell output and TIL tumor reactivity. To exploit this, we used a CTLA-4-blocking antibody, added during the initial TIL culture, and found that the blockade of CTLA-4 favored the propagation of CD8+ TILs from ovarian tumor fragments. Interestingly, adding the CTLA-4 blocking antibody in the initial phase of the TIL culture resulted in more potent anti-tumor TILs in comparison to standard TIL cultures. This phenotype was preserved during the rapid expansion phase. Thus, targeting CTLA-4 within the intact tumor microenvironment of tumor fragments enriches tumor-reactive TILs and may improve clinical outcome of TIL-based ACT in ovarian cancer.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
10
issue
1
article number
3914
publisher
Nature Publishing Group
external identifiers
  • scopus:85080962592
  • pmid:32127601
ISSN
2045-2322
DOI
10.1038/s41598-020-60738-4
language
English
LU publication?
yes
id
4e03c241-c547-4606-a33d-9b5347f7ecd7
date added to LUP
2020-03-17 09:53:35
date last changed
2024-06-13 12:49:09
@article{4e03c241-c547-4606-a33d-9b5347f7ecd7,
  abstract     = {{<p>Adoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) can induce durable complete tumor regression in patients with advanced melanoma. Efforts are currently underway to expand this treatment modality to other cancer types. In the microenvironment of ovarian cancer, the engagement of co-inhibitory immune checkpoint molecules such as CTLA-4 can lead to the inactivation of TILs. Thus, approaches that directly manipulate co-inhibitory pathways within the tumor microenvironment might improve the expansion of tumor-reactive TILs. The initial expansion of TILs for ACT from tumor fragments provides a window of opportunity to manipulate an intact tumor microenvironment and improve CD8<sup>+</sup> T-cell output and TIL tumor reactivity. To exploit this, we used a CTLA-4-blocking antibody, added during the initial TIL culture, and found that the blockade of CTLA-4 favored the propagation of CD8<sup>+</sup> TILs from ovarian tumor fragments. Interestingly, adding the CTLA-4 blocking antibody in the initial phase of the TIL culture resulted in more potent anti-tumor TILs in comparison to standard TIL cultures. This phenotype was preserved during the rapid expansion phase. Thus, targeting CTLA-4 within the intact tumor microenvironment of tumor fragments enriches tumor-reactive TILs and may improve clinical outcome of TIL-based ACT in ovarian cancer.</p>}},
  author       = {{Friese, Christina and Harbst, Katja and Borch, Troels Holz and Westergaard, Marie Christine Wulff and Pedersen, Magnus and Kverneland, Anders and Jönsson, Göran and Donia, Marco and Svane, Inge Marie and Met, Özcan}},
  issn         = {{2045-2322}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{CTLA-4 blockade boosts the expansion of tumor-reactive CD8<sup>+</sup> tumor-infiltrating lymphocytes in ovarian cancer}},
  url          = {{http://dx.doi.org/10.1038/s41598-020-60738-4}},
  doi          = {{10.1038/s41598-020-60738-4}},
  volume       = {{10}},
  year         = {{2020}},
}