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

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

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.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / physiology*
  • Cancer Vaccines / immunology*
  • Cell Growth Processes
  • Cell Line, Tumor
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / therapeutic use
  • Female
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Lymphocyte Activation
  • Mammary Neoplasms, Animal / drug therapy*
  • Mammary Neoplasms, Animal / immunology
  • Mammary Neoplasms, Experimental / drug therapy*
  • Mammary Neoplasms, Experimental / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Neoplasm Transplantation
  • Tumor Burden
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1 / genetics*

Substances

  • Cancer Vaccines
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1
  • Vtcn1 protein, mouse
  • Deoxycytidine
  • gemcitabine