Akt and SHP-1 are DC-intrinsic checkpoints for tumor immunity.
BM-derived DC (BMDC) are powerful antigen-presenting cells. When loaded with immune complexes (IC), consisting of tumor antigens bound to antitumor antibody, BMDC induce powerful antitumor immunity in mice. However, attempts to employ this strategy clinically with either tumor-associated DC (TADC) or monocyte-derived DC (MoDC) have been disappointing. To investigate the basis for this phenomenon, we compared the response of BMDC, TADC, and MoDC to tumor IgG-IC. Our findings revealed, in both mice and humans, that upon exposure to IgG-IC, BMDC internalized the IC, increased costimulatory molecule expression, and stimulated autologous T cells. In contrast, TADC and, surprisingly, MoDC remained inert upon contact with IC due to dysfunctional signaling following engagement of Fcγ receptors. Such dysfunction is associated with elevated levels of the Src homology region 2 domain-containing phosphatase-1 (SHP-1) and phosphatases regulating Akt activation. Indeed, concomitant inhibition of both SHP-1 and phosphatases that regulate Akt activation conferred upon TADC and MoDC the capacity to take up and process IC and induce antitumor immunity in vivo. This work identifies the molecular checkpoints that govern activation of MoDC and TADC and their capacity to elicit T cell immunity.
Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.|Department of Pathology, The Sackler School of Medicine, Tel-Aviv University, Ramat Aviv, Israel.
Yaron
Y
Carmi
Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.|Program in Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.
Tyler R
TR
Prestwood
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, USA.
Matthew H
MH
Spitzer
Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.|Program in Immunology, Stanford University School of Medicine, Stanford, California, USA.
Ian L
IL
Linde
Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Jonathan
J
Chabon
Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
Nathan E
NE
Reticker-Flynn
Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
Nupur
N
Bhattacharya
Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
Hong
H
Zhang
Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
Xiangyue
X
Zhang
Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
Pamela A
PA
Basto
Division of General Thoracic Surgery, Baylor College of Medicine, Houston, Texas, USA.
Bryan M
BM
Burt
Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
Michael N
MN
Alonso
Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
Edgar G
EG
Engleman
D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology; D009364:Neoplasm Recurrence, Local; D009374:Neoplasms, Experimental / Q000276:immunology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology; D059016:Tumor Microenvironment
D000936:Antigen-Antibody Complex; D000951:Antigens, Neoplasm; D051057:Proto-Oncogene Proteins c-akt; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse