Advertisement

Myxoma virus suppresses proliferation of activated T lymphocytes yet permits oncolytic virus transfer to cancer cells

Nancy Y. Villa, Clive H. Wasserfall, Amy Meacham, Elizabeth Wise, Winnie Chan, John R. Wingard, Grant McFadden and Christopher R. Cogle

Key points

  • MYXV binds human T lymphocytes but does not enter and infect T cells until after activation.

  • MYXV-infected T lymphocytes proliferate less and secrete less inflammatory cytokines; but effectively deliver oncolytic virus to augment GVM.

Abstract

Allogeneic hematopoietic cell transplant (allo-HCT) can be curative for certain hematological malignancies, but the risk of graft-versus-host disease (GVHD) is a major limitation for wider application. Ideally, strategies to improve allo-HCT would involve suppression of T lymphocytes that drive GVHD while sparing those that mediate graft-versus-malignancy (GVM). Recently, using a xenograft model we serendipitously discovered that MYXV prevented GVHD while permitting GVM. In this study, we show that MYXV binds to resting, primary human T lymphocytes but will only proceed into active virus infection after the T cells receive activation signals. MYXV-infected T lymphocytes exhibited impaired proliferation after activation with reduced expression of interferon-γ, interleukin-2 and soluble IL-2Rα, but unaffected IL-4 and IL-10. MYXV suppressed T cell proliferation in two patterns (full vs. partial) depending on the donor. In terms of GVM, we show that MYXV-infected activated human T lymphocytes effectively deliver live oncolytic virus to human multiple myeloma cells, thus augmenting GVM by delivery of active oncolytic virus to residual cancer cells. Given this dual capacity of reducing GVHD plus increasing the anti-tumor effectiveness of GVM, ex vivo virotherapy with MYXV may be a promising clinical adjunct to allo-HCT regimens.

  • Submitted July 16, 2014.
  • Accepted April 13, 2015.