CD28-mediated pro-survival signaling induces chemotherapeutic resistance in multiple myeloma.
Chemotherapeutic resistance remains a significant hurdle in the treatment of multiple myeloma (MM) and is significantly mediated by interactions between MM cells and stromal cells of the bone marrow microenvironment. Despite the importance of these interactions, the specific molecules and downstream signaling components involved remain incompletely understood. We have previously shown that the prototypic T-cell costimulatory receptor CD28, which is also expressed on MM cells, is a key mediator of MM survival and apoptotic resistance. Crosslinking CD28 by agonistic antibodies or myeloid dendritic cells (DC; these express the CD28 ligands CD80/CD86) prevents apoptosis caused by chemotherapy or serum withdrawal. We now report that CD28 pro-survival signaling is dependent upon downstream activation of phosphatidyl-inositol 3-kinase/Akt, inactivation of the transcription factor FoxO3a, and decreased expression of the pro-apoptotic molecule Bim. Conversely, blocking the CD28-CD80/CD86 interaction between MM cells and DC in vitro abrogates the DC's ability to protect MM cells against chemotherapy-induced death. Consistent with these observations, in vivo blockade of CD28-CD80/CD86 in the Vk*MYC murine myeloma model sensitizes MM cells to chemotherapy and significantly reduces tumor burden. Taken together, our findings suggest that CD28 is an important mediator of MM survival during stress and can be targeted to overcome chemotherapy resistance.
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY;
Megan E
ME
Murray
The Department of Hematology and Medical Oncology and the Winship Cancer Institute, Emory University, Atlanta, GA;
Catherine M
CM
Gavile
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY;
Jayakumar R
JR
Nair
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY;
Chandana
C
Koorella
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY;
Louise M
LM
Carlson
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY;
Daniela
D
Buac
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY;
Adam
A
Utley
Mayo Clinic Arizona, Comprehensive Cancer Center, Scottsdale, AZ; and.
Marta
M
Chesi
Mayo Clinic Arizona, Comprehensive Cancer Center, Scottsdale, AZ; and.
P Leif
PL
Bergsagel
The Department of Hematology and Medical Oncology and the Winship Cancer Institute, Emory University, Atlanta, GA;
Lawrence H
LH
Boise
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY; Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY.
Kelvin P
http://orcid.org/0000-0003-2587-0734
KP
Lee
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018106:CD28 Antigens / Q000276:immunology / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics
D000906:Antibodies; D000970:Antineoplastic Agents; D018106:CD28 Antigens; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt