MICA/B antibody induces macrophage-mediated immunity against acute myeloid leukemia
Pedro Henrique Alves da Silva1, Samantha Xing1, Andriana G Kotini2,3,4
1Precision Immunology Institute.
Abstract:
Acute myeloid leukemia (AML) is a clonal hematopoietic stem and progenitor cell malignancy characterized by poor clinical outcomes. Major histocompatibility complex class I polypeptide-related sequence A and B (MICA/B) are stress proteins expressed by cancer cells, and antibody-mediated inhibition of MICA/B shedding represents a novel approach to stimulate immunity against cancers. We found that the MICA/B antibody 7C6 potently inhibits the outgrowth of AML in 2 models in immunocompetent mice. Macrophages were essential for therapeutic efficacy, and 7C6 triggered antibody-dependent phagocytosis of AML cells. Furthermore, we found that romidepsin, a selective histone deacetylase inhibitor, increased MICB messenger RNA in AML cells and enabled subsequent stabilization of the translated protein by 7C6. This drug combination substantially increased surface MICA/B expression in a human AML line, pluripotent stem cell-derived AML blasts and leukemia stem cells, as well as primary cells from 3 untreated patients with AML. Human macrophages phagocytosed AML cells following treatment with 7C6 and romidepsin, and the combination therapy lowered leukemia burden in a humanized model of AML. Therefore, inhibition of MICA/B shedding promotes macrophage-driven immunity against AML via Fc receptor signaling and synergizes with an epigenetic regulator. These results provide the rationale for the clinical testing of this innovative immunotherapeutic approach for the treatment of AML.
Insights
An antibody targeting MICA/B proteins inhibits acute myeloid leukemia (AML) growth by enhancing macrophage phagocytosis. Combining this antibody with romidepsin, a histone deacetylase inhibitor, boosts therapeutic effects against AML.
Area of Science:
- Immunology
- Oncology
- Hematology
Background:
- Acute myeloid leukemia (AML) is a serious blood cancer with poor outcomes.
- MICA/B proteins are stress molecules on cancer cells; inhibiting their shedding is a potential cancer immunotherapy.
- Antibody-mediated inhibition of MICA/B shedding is a novel strategy to enhance anti-cancer immunity.
Purpose of the Study:
- To investigate the efficacy of MICA/B antibody 7C6 in treating AML.
- To explore the synergistic effect of romidepsin with MICA/B antibody 7C6 in AML treatment.
- To elucidate the role of macrophages in the therapeutic mechanism.
Main Methods:
- Testing MICA/B antibody 7C6 in murine AML models.
- Evaluating the combination of 7C6 with romidepsin in human AML cell lines and patient samples.
- Assessing antibody-dependent phagocytosis by macrophages.
- Utilizing a humanized mouse model to evaluate in vivo efficacy.
Main Results:
- The MICA/B antibody 7C6 demonstrated potent inhibition of AML outgrowth in mice.
- Macrophages were crucial for the therapeutic effect, mediating antibody-dependent phagocytosis of AML cells.
- Romidepsin enhanced surface MICA/B expression, leading to synergistic anti-leukemic activity with 7C6.
- The combination therapy reduced leukemia burden in a humanized AML model.
Conclusions:
- Inhibition of MICA/B shedding promotes macrophage-driven immunity against AML.
- The combination of MICA/B antibody 7C6 and romidepsin shows significant therapeutic potential for AML.
- This approach provides a rationale for clinical trials in AML patients.
