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.

Flow cytometry data acquisition and cell sorting were performed at the Stanford Blood Center Flow Cytometry Facility. We thank Lorna Tolentino, Nancy Wu, and Okmi Choi for expert technical support. Research reported in this publication was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Breast Cancer Research Program under award number W81XWH-15-1-0037; by the National Cancer Institute of the National Institutes of Health under award numbers R01CA196657 (to EGE), F30CA196145 (to TRP), F31CA189331 (to MHS), F31CA196029 (to ILL), and F32CA189408 (to NERF); and by the National Institute of General Medical Sciences of the National Institutes of Health under award number T32GM007365, with additional support from Stanford School of Medicine (to TRP). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense.