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CD28-mediated pro-survival signaling induces chemotherapeutic resistance in multiple myeloma

Megan E Murray1, Catherine M Gavile2, Jayakumar R Nair1

  • 1Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY;

Blood
|May 1, 2014
PubMed

Insights

Targeting the CD28 pathway in multiple myeloma (MM) can overcome chemotherapy resistance. Blocking CD28 interactions with dendritic cells (DCs) sensitizes MM cells to treatment and reduces tumor burden.

Area of Science:

  • Immunology
  • Oncology
  • Cell Biology

Background:

  • Chemotherapy resistance in multiple myeloma (MM) is a major challenge, partly due to interactions within the bone marrow microenvironment.
  • The T-cell costimulatory receptor CD28, present on MM cells, has been identified as a key factor in MM cell survival and resistance to apoptosis.

Purpose of the Study:

  • To investigate the role of CD28 signaling in mediating MM cell survival and resistance to chemotherapy.
  • To elucidate the downstream signaling pathways involved in CD28-mediated protection of MM cells.

Main Methods:

  • Utilized in vitro co-culture systems of MM cells and dendritic cells (DCs) with and without CD28-CD80/CD86 blockade.
  • Employed Western blotting and gene expression analysis to assess signaling pathway activation (Akt, FoxO3a, Bim).
  • Tested the efficacy of in vivo CD28-CD80/CD86 blockade in the Vk*MYC murine myeloma model.

Main Results:

  • CD28 crosslinking by agonistic antibodies or DCs protected MM cells from chemotherapy-induced apoptosis.
  • CD28 pro-survival signaling involved activation of phosphatidyl-inositol 3-kinase/Akt, inactivation of FoxO3a, and reduced Bim expression.
  • In vitro and in vivo blockade of CD28-CD80/CD86 interactions sensitized MM cells to chemotherapy and reduced tumor burden.

Conclusions:

  • CD28 is a critical mediator of multiple myeloma cell survival under stress conditions.
  • Targeting the CD28-CD80/CD86 axis offers a promising strategy to overcome chemotherapy resistance in MM.

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