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Cancer Immunol Immunother. 2017 Apr;66(4):491-502. doi: 10.1007/s00262-016-1950-2. Epub 2017 Jan 10.

Synergistic effects of host B7-H4 deficiency and gemcitabine treatment on tumor regression and anti-tumor T cell immunity in a mouse model.

Leung J1,2, St-Onge P1,3, Stagg J4, Suh WK5,6,7,8,9.

Author information

1
Institut de recherches cliniques de Montréal (IRCM), 110 avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada.
2
Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada.
3
Département de Médecine (Programmes de Biologie Moléculaire), Université de Montréal, Montréal, QC, Canada.
4
Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Institut du Cancer de Montréal, Faculté de Pharmacie, Université de Montréal, Québec, Canada.
5
Institut de recherches cliniques de Montréal (IRCM), 110 avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada. woong-kyung.suh@ircm.qc.ca.
6
Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada. woong-kyung.suh@ircm.qc.ca.
7
Département de Médecine (Programmes de Biologie Moléculaire), Université de Montréal, Montréal, QC, Canada. woong-kyung.suh@ircm.qc.ca.
8
Département de Médecine, Université de Montréal, Montréal, QC, Canada. woong-kyung.suh@ircm.qc.ca.
9
Département de Microbiologie, Infectiologie, et Immunologie, Université de Montréal, Montréal, QC, Canada. woong-kyung.suh@ircm.qc.ca.

Abstract

B7-H4 (B7x/B7S1), a B7 family inhibitor of T cell activity, is expressed in multiple human cancers and correlates with decreased infiltrating lymphocytes and poor prognosis. In murine models, tumor-expressed B7-H4 enhances tumor growth and reduces T cell immunity, and blockade of tumor-B7-H4 rescues T cell activity and lowers tumor burden. This implicates B7-H4 as a target for cancer immunotherapy, yet limits the efficacy of B7-H4 blockade exclusively to patients with B7-H4+ tumors. Given the expression of B7-H4 on host immune cells, we have previously shown that BALB/c mice lacking host B7-H4 have enhanced anti-tumor profiles, yet similar 4T1 tumor growth relative to control. Given that T cell-mediated immunotherapies work best for tumors presenting tumor-associated neoantigens, we further investigated the function of host B7-H4 in the growth of a more immunogenic derivative, 4T1-12B, which is known to elicit strong anti-tumor CD8 T cell responses due to expression of a surrogate tumor-specific antigen, firefly luciferase. Notably, B7-H4 knockout hosts not only mounted greater tumor-associated anti-tumor T cell responses, but also displayed reduced tumors. Additionally, B7-H4-deficiency synergized with gemcitabine to further inhibit tumor growth, often leading to tumor eradication and the generation of protective T cell immunity. These findings imply that inhibition of host B7-H4 can enhance anti-tumor T cell immunity in immunogenic cancers, and can be combined with other anti-cancer therapies to further reduce tumor burden regardless of tumor-B7-H4 positivity.

KEYWORDS:

B7-H4; Cancer immunotherapy; Immune checkpoint blockade; T cell immunity

PMID:
28074226
DOI:
10.1007/s00262-016-1950-2
[Indexed for MEDLINE]

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