Host B7-H4 regulates antitumor T cell responses through inhibition of myeloid-derived suppressor cells in a 4T1 tumor transplantation model

J Immunol. 2013 Jun 15;190(12):6651-61. doi: 10.4049/jimmunol.1201242. Epub 2013 May 17.

Abstract

B7-H4, a member of the B7 family of T cell immunomodulatory proteins, has been shown to inhibit T cell responses and neutrophil expansion during bacterial infections. However, the role of B7-H4 in the immune response during tumor growth has been unclear. In this study, we examined the host immune responses in B7-H4-deficient (knockout [KO]) or sufficient (wild-type [WT]) BALB/cJ mice upon transplantation of murine 4T1 carcinoma cells that had little B7-H4 expression. We reveal that host B7-H4 not only dampens the antitumor Th1 responses, but also inhibits the protumor function of myeloid-derived suppressor cells (MDSC). We observed increased expression of both antitumor immune effectors and protumor MDSC-associated transcripts in 4T1 tumors grown in B7-H4 KO mice compared with those grown in WT hosts. Consistently, MDSCs derived from B7-H4 KO mice suppressed T cell proliferation more potently than their WT counterparts. Although the primary growth of 4T1 tumors in B7-H4 KO hosts was similar to that in WT mice, tumors that had grown in B7-H4 KO hosts grew much slower than those from WT mice when subsequently transplanted into WT hosts. Importantly, this differential tumor growth during the secondary transplantation was abrogated when recipient mice lacked T cells, indicating that the immune environment in B7-H4 KO hosts allowed outgrowth of 4T1 tumors with reduced immune-evasive capacities against T cells. Thus, B7-H4 can inhibit both antitumor T cells and protumor MDSCs, influencing the immune-evasive character of the outgrowing tumors. These factors should be considered if B7-H4 blockade is to be used for cancer immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Separation
  • Flow Cytometry
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Myeloid Cells / immunology*
  • Neoplasm Transplantation
  • Neoplasms, Experimental / immunology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes / immunology*
  • V-Set Domain-Containing T-Cell Activation Inhibitor 1 / immunology*

Substances

  • V-Set Domain-Containing T-Cell Activation Inhibitor 1
  • Vtcn1 protein, mouse