Tumor antigen-targeting monoclonal antibody-based immunotherapy: Orchestrating combined strategies for the development of long-term antitumor immunity

Michaud, Henri-Alexandre; Eliaou, Jean‐François; Lafont, Virginie; Bonnefoy, Nathalie; Gros, Laurent

doi:10.4161/21624011.2014.955684

Cited by 47 publications

(35 citation statements)

References 67 publications

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“…Since ADCP can also be mediated by DCs (Michaud et al, 2014), we induced ADCP in monocyte-derived DCs (mo-DC) and found that PD-L1 and IDO were upregulated after ADCP, which could be inhibited by blocking FcgRs or IL-1b ( Figure 3E). In addition, blockade of PD-L1 and IDO significantly increased perforin expression in NK cells co-cultured with mo-DCs after ADCP ( Figure 3F).…”

Section: Il-1b Upregulates Pd-l1 and Ido In Adcp Macrophagesmentioning

confidence: 99%

“…Immune responses mediated by Fc gamma receptors (FcgRs) on the innate immune cells are critically involved and determine the efficacy of therapeutic antibodies (Clynes et al, 2000). Interaction between antibody Fc fragment and FcgRs eliminates antibody-bound tumor cells via antibody-dependent cellular cytotoxicity (ADCC) mainly by natural killer (NK) cells, or via antibody-dependent cellular phagocytosis (ADCP) mainly by macrophages (Clynes et al, 2000;Michaud et al, 2014). ADCC has been studied extensively and is critical for the tumoricidal effects of therapeutic antibodies, in which immune cells bind to cancer cells via antibodies and lyse them by releasing perforin and granzymes (Zhu et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Immune Checkpoint Inhibition Overcomes ADCP-Induced Immunosuppression by Macrophages

Zhao

Xing

et al. 2018

Cell

219

173

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Graphical AbstractHighlights d Macrophages are immunosuppressive because of upregulated PD-L1 and IDO after ADCP d AIM2 is recruited to phagosomes and activated by tumor DNA in ADCP macrophages d AIM2 cleaves cGAS and upregulates PD-L1 and IDO by caspase-1/IL-1b d Synergistic effects between therapeutic antibodies and ICIs are macrophage dependent SUMMARY Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) critically contribute to the efficacy of anti-tumor therapeutic antibodies. We report here an unexpected finding that macrophages after ADCP inhibit NK cell-mediated ADCC and T cell-mediated cytotoxicity in breast cancers and lymphomas. Mechanistically, AIM2 is recruited to the phagosomes by FcgR signaling following ADCP and activated by sensing the phagocytosed tumor DNAs through the disrupted phagosomal membrane, which subsequently upregulates PD-L1 and IDO and causes immunosuppression. Combined treatment with anti-HER2 antibody and inhibitors of PD-L1 and IDO enhances antitumor immunity and anti-HER2 therapeutic efficacy in mouse models. Furthermore, neoadjuvant trastuzumab therapy significantly upregulates PD-L1 and IDO in the tumor-associated macrophages (TAMs) of HER2 + breast cancer patients, correlating with poor trastuzumab response. Collectively, our findings unveil a deleterious role of ADCP macrophages in cancer immunosuppression and suggest that therapeutic antibody plus immune checkpoint blockade may provide synergistic effects in cancer treatment.

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Section: Il-1b Upregulates Pd-l1 and Ido In Adcp Macrophagesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immune Checkpoint Inhibition Overcomes ADCP-Induced Immunosuppression by Macrophages

Zhao

Xing

et al. 2018

Cell

219

173

View full text Add to dashboard Cite

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“…In rare instances, local radiation treatment can trigger a systemic or “abscopal” immune response at non-radiated tumor sites in patients with metastatic disease. Tumor-specific mAbs are commonly designed to antagonize a target molecule on tumor cells but may also initiate a tumor-directed immune response by engaging Fcγ receptors (FcγR) on innate immune cells (2). Upon binding the Fc portion of mAb, these immune cells can destroy mAb-bound tumor cells through the process of antibody-dependent cell-mediated cytotoxicity (ADCC).…”

Section: Introductionmentioning

confidence: 99%

In SituTumor Vaccination by Combining Local Radiation and Tumor-Specific Antibody or Immunocytokine Treatments

et al. 2016

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Interest in combining radiotherapy and immune checkpoint therapy is growing rapidly. In this study, we explored a novel combination of this type to augment anti-tumor immune responses in preclinical murine models of melanoma, neuroblastoma, and head and neck squamous cell carcinoma. Cooperative effects were observed with local radiotherapy and intratumoral injection of tumor-specific antibodies, arising in part from enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). We could improve this response by combining radiation with intratumoral injection of an IL-2-linked tumor-specific antibody (termed here an immunocytokine), resulting in complete regression of established tumors in most animals associated with a tumor-specific memory T cell response. Given the T cell response elicited by combined local radiation and intratumoral immunocytokine, we tested the potential benefit of adding this treatment to immune checkpoint blockade. In mice bearing large primary tumors or disseminated metastases, the triple-combination of intratumoral immunocytokine, radiation, and systemic anti-CTLA-4 improved primary tumor response and animal survival compared to combinations of any two of these three interventions. Taken together, our results show how combining radiation and intratumoral immunocytokine in murine tumor models can eradicate large tumors and metastases, eliciting an in situ vaccination effect that can be leveraged further by T cell checkpoint blockade, with immediate implications for clinical evaluation.

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“…13 Indeed, STAT3 inhibitors can be advantageously combined with immunogenic cell death (ICD)-inducing chemotherapeutic agents. 13 Given the clinical impact of ICD inducers, [15][16][17][18][19][20][21][22] it will be important to explore this possibility in properly designed trials.…”

mentioning

confidence: 99%

STAT3 inhibition for cancer therapy: Cell-autonomous effects only?

2016

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Tumor antigen-targeting monoclonal antibody-based immunotherapy: Orchestrating combined strategies for the development of long-term antitumor immunity

Cited by 47 publications

References 67 publications

Immune Checkpoint Inhibition Overcomes ADCP-Induced Immunosuppression by Macrophages

Immune Checkpoint Inhibition Overcomes ADCP-Induced Immunosuppression by Macrophages

In SituTumor Vaccination by Combining Local Radiation and Tumor-Specific Antibody or Immunocytokine Treatments

STAT3 inhibition for cancer therapy: Cell-autonomous effects only?

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