ACBP/DBI Neutralization Stimulates Anticancer Immune Responses by Upregulating Lamin A in T Cells

Acyl CoA binding protein (ACBP, encoded by the gene diazepam binding inhibitor, DBI) is a tissue stress hormone involved in pathological aging that mediates immunosuppression. The antibody-mediated neutralization of ACBP/DBI enhances anticancer immune responses in the context of chemoimmunotherapy. ACBP/DBI inhibition also upregulates the expression of the anti-aging gene Lmna coding for Lamin A in tumor-infiltrating T lymphocytes. This study was designed to explore the role of Lmna in the anticancer effects of ACBP/DBI neutralization.

We generated mice lacking Lmna expression in T lymphocytes due to a conditional knockout. Mice bearing orthotopic (cutaneous) MCA205 fibrosarcomas were treated with an anti-ACBP/DBI monoclonal antibody in the context of chemoimmuntherapy (oxaliplatin combined with a PD-1 blocking antibody), and tumor growth was monitored.

As compared to immunocompetent control mice, in which ACBP/DBI neutralization plus chemoimmunotherapy was highly efficient in reducing MCA205 growth, mice lacking ACBP/DBI in T cells largely failed to respond to the therapeutic intervention. This result was undistinguishably observed in both female and male mice.

Altogether, these results indicate that Lmna expression by T lymphocytes is required for the anticancer effects of the combination of chemoimmunotherapy and ACBP/DBI neutralization. We conclude that lamin A, a factor required for optimal T cell activation, is causally involved in the immunostimulatory effects of ACBP/DBI neutralization.