Multiple Antitumor Mechanisms Downstream of Prophylactic Regulatory T-Cell Depletion

Abstract

Several reports have shown that prophylactic depletion of regulatory T cells (Treg) using various monoclonal antibodies (mAb) in mice can stimulate potent antitumor immune responses and prevent tumor development. These same depletion methods do not significantly suppress tumor growth in a therapeutic setting. Although different strategies to deplete FoxP3 + Treg have been used, no study has systematically compared these qualitatively for the effector mechanisms they each liberate. Herein, using prophylactic depletion of FoxP3 + Tregs with either anti-CD4, anti-CD25, or anti-FR4 mAbs, we have compared the cellular and effector requirements for elimination of the renal carcinoma RENCA and prevention of methylcholanthrene-induced fibrosarcoma.Collectively from these two models, it was clear that CD8 + T cells and natural killer cells played an important role downstream of Treg depletion. However, whereas all three mAbs quantitatively depleted FoxP3 + T cells to a similar extent, subtle differences in the downstream mechanisms of tumor control existed for all three approaches. In general, neutralization of any lymphocyte subset or effector mechanism was insufficient to alter tumor suppression initiated by Treg depletion, and in some settings, the neutralization of multiple effector mechanisms failed to prevent tumor rejection. These studies reveal that Tregs control multiple redundant elements of the immune effector response capable of inhibiting tumor initiation and underscore the importance of effectively targeting these cells in any cancer immunotherapy.

Selective Depletion of Foxp3+ Regulatory T Cells Improves Effective Therapeutic Vaccination against Established Melanoma

“…Selective depletion of Foxp3 + Tregs leads to the regression of established tumors Several studies have shown that removal of CD25 + Tregs using depleting antibodies before the inoculation of tumor cells leads to their efficient rejection (13)(14)(15)(16)(17)(18)28); however, no tumor regression was observed in the majority of studies where CD25 + Tregs were depleted after inoculation of tumor cells (13,19,20). This therapeutic failure is most likely due to a concomitant elimination of tumor-specific, CD25-expressing effector T cells (13,19) or to the persistence of CD25 − Tregs (12), which cannot be targeted by anti-CD25…”

“…Accordingly, the main obstacle tempering successful immunotherapies and active vaccination might be the migration of Treg into tumors and their suppression of effective antitumor immune responses in the tumor microenvironment (2,9,11,12). Various groups have already investigated whether Treg removal using the depleting anti-CD25 antibody PC61 in mice might improve antitumor immunity, and it was shown that depletion of Tregs before the inoculation of tumor cells led to their efficient rejection (13)(14)(15)(16)(17)(18). In contrast, Treg depletion simultaneously with or after tumor inoculation resulted in no tumor regression (13,19,20), likely because the administered depleting antibodies also removed CD25-expressing effector T cells and CD25 − Foxp3 + Tregs persisted.…”

A dual role for autophagy in a murine model of lung cancer

“…Inactivation Tregs in vivo was performed as previously reported 42,43 . Briefly, anti-CD25 (500 mg per mouse, eBioscience, #16-0251), anti-FR4 (25 mg per mouse; Biolegend, #125102) or a rat IgG1 isotype control Ab (eBioscience, #16-4301; Biolegend, #400622) were injected once at day À 1 before AdCre inhalation.…”

Interferon-dependent IL-10 production by Tregs limits tumor Th17 inflammation

“…Through a variety of effector mechanisms, Tregs control inflammation and immunity in multiple contexts, including the regulation of Th1-, Th2-, and Th17-type inflammatory responses (8)(9)(10)(11). In preclinical models of both prophylactic and therapeutic cancer therapy, Tregs limit the generation of Th1 responses that drive CD8 + T cells and IFN-γ-dependent antitumor immunity (12)(13)(14)(15)(16). Furthermore, the mechanism of action of the humanized anti-CTLA-4 monoclonal antibody ipilimumab (Bristol Myers Squibb), which was given US FDA approval in 2011 (17) for treatment of advanced melanoma, depends on its ability to block Tregs and release APCs from Treg inhibition.…”