What is the role of all-trans retinoic acid (ATRA) in modulating myeloid-derived suppressor cells (MDSCs) in cancer treatment?

Role of All-Trans Retinoic Acid (ATRA) in Modulating Myeloid-Derived Suppressor Cells (MDSCs) in Cancer Treatment

ATRA has a dual role in cancer treatment, serving as a primary therapeutic agent in acute promyelocytic leukemia (APL) through differentiation therapy, while potentially enhancing metastatic tumor growth in some solid cancers by differentiating MDSCs into more potent immunosuppressive macrophages.

ATRA in Acute Promyelocytic Leukemia (APL)

ATRA has revolutionized the treatment of APL, a subtype of acute myeloid leukemia, through its ability to induce differentiation of leukemic promyelocytes.

Mechanism of Action in APL

• ATRA binds to nuclear retinoic acid receptors (RARs), particularly RAR-alpha, which is rearranged in APL due to the t(15;17) translocation 1
• Promotes terminal differentiation of leukemic promyelocytes rather than cell death
• Reverses the maturation arrest induced by the PML-RARA fusion protein 1

Clinical Application in APL

• ATRA is a cornerstone of APL treatment, used in both induction and consolidation therapy 2
• For low/intermediate-risk APL (WBC ≤10,000/mcL):
  • ATRA (45 mg/m² in 2 divided doses daily) combined with arsenic trioxide (ATO) is now standard of care 2
  • ATRA + ATO combination yields high-quality remission without chemotherapy 2
• For high-risk APL (WBC >10,000/mcL):
  • ATRA combined with anthracycline-based chemotherapy 2

Clinical Outcomes in APL

• Complete remission rates exceed 90% with ATRA-based regimens 2
• Early initiation of ATRA prevents lethal bleeding complications 2
• More than 75% of patients can be cured with ATRA + chemotherapy combinations 3
• ATRA + ATO has shown superior event-free survival compared to ATRA + idarubicin (AIDA) regimen 2

ATRA and MDSCs in Solid Tumors

The role of ATRA in modulating MDSCs in solid tumors is complex and potentially problematic.

Effect on MDSC Differentiation

• ATRA promotes differentiation of immature CD11b+Gr1+F4/80-Ly6C(mid)Ly6G+ MDSCs into mature CD11b+Gr1-F4/80+ macrophages 4
• This differentiation was initially thought to be beneficial by reducing immunosuppressive MDSCs

Unexpected Consequences

• ATRA-induced differentiation of MDSCs into macrophages can enhance metastatic tumor growth 4
• Mature F4/80+Ly6C-Ly6G- macrophages are up to 30-fold more potent immune suppressors than immature MDSCs 4
• These macrophages produce higher levels of reactive oxygen species (ROS), contributing to their superior immunosuppressive abilities 4

Clinical Implications for Solid Tumors

• ATRA treatment may potentially promote metastasis in certain cancers like breast cancer 4
• This contradicts the initial hypothesis that differentiating MDSCs would reduce immunosuppression
• Caution is warranted when considering ATRA for modulating myeloid cell differentiation in solid tumors, particularly breast cancer with lung metastases 4

Therapeutic Considerations

APL Treatment

• Start ATRA immediately upon suspicion of APL, without waiting for genetic confirmation 2
• Monitor for APL differentiation syndrome and coagulopathy 2
• Maintain platelet counts at minimum 30-50 G/l and fibrinogen in normal range (100-150 mg/dl) 2

Solid Tumor Considerations

• ATRA is being investigated in various solid tumors including Kaposi's sarcoma, head and neck squamous cell carcinoma, ovarian carcinoma, bladder cancer, and neuroblastoma 5
• Consider alternative approaches to target myeloid cells collectively rather than inducing their differentiation 4
• ROS inhibitors may be useful in promoting antitumor immune responses by counteracting the immunosuppressive effects of macrophages 4

Pitfalls and Caveats

1. APL Differentiation Syndrome: Monitor for respiratory distress, fever, weight gain, pulmonary infiltrates, and pleural/pericardial effusions during ATRA treatment 2

2. Premature Response Assessment: Avoid premature morphologic and molecular assessment (day 10-14 marrow) as it can be misleading; patients often remain molecularly positive at the end of induction 2

3. MDSC Differentiation in Solid Tumors: Be aware that ATRA-induced differentiation of MDSCs may enhance rather than reduce immunosuppression in the tumor microenvironment 4

4. Treatment Consistency: To achieve expected results, use treatment regimens consistently through all components and do not mix induction from one trial with consolidation from another 2

In conclusion, while ATRA has been transformative in APL treatment, its application in modulating MDSCs in solid tumors requires careful consideration due to the potential for enhanced immunosuppression through macrophage differentiation.