Summary of biological impact of therapeutic agents on macrophages in FL
| Agent . | Molecular mechanism . | Biological impact . | References . |
|---|---|---|---|
| Low-dose radiation | Induction of TLR4, STAT1, ICGR1A, C1q, and APOE in macrophages | Increased macrophage phagocytosis | 26 |
| High-dose radiation | Induction of CD80, CD86, and HLA-DR in macrophages Downregulation of CD163, MRC1, VCAN, and IL-10 Preservation of MMP-2 and MMP-9 activity | Increased macrophage phagocytosis but decreased macrophage production of proinflammatory (antitumoral) cytokines | 25 |
| CTX | Induction of ATF4-mediated paracrine secretion of VEGF-A in lymphoma cells CD47 downregulation | Increased macrophage infiltration and phagocytosis | 28 |
| DOX | Increased tumor immunogenicity Macrophage sparing | Increased macrophage production of proinflammatory (antitumoral) cytokines | 32,33 |
| Vincristine | NLRP3 inflammasome induction Increased production of proinflammatory cytokines (IL-1β, IL-6, and CXCL1) | Increased macrophage production of proinflammatory (antitumoral) cytokines | 34 |
| Bendamustine | Unknown | Unknown | |
| Rituximab | Interaction with macrophage’s FcγRIV, FcγRIII, and FcγRI | Increased ADCC and ADCP | 45,46 |
| Obinutuzumab | Interactions with FcγRIIIa | Increased ADCC and ADCP | 48,51–53 |
| Lenalidomide | Unknown in FL | Unknown in FL | 58,95 |
| BTK inhibitors (ibrutinib) | Downregulation of CXCL12, CXCL13, CCL19, and VEGF Dephosphorylation of ERK1/2, AKT, and PLCγ2 Inhibition of JAK2 | Decreased interaction between protumoral macrophages (M2) and FL cells Increased ADCP | 63,66–68 |
| PI3K inhibitors (idelalisib and duvelisib) | Reduction of BAD phosphorylation via Ser136 Downregulation of BFL-1 Stimulation of NF-κB activation leading to C/EBPβ inactivation | Restored FL dependence on BCL-2 Increased macrophage polarization to an M1 phenotype | 76–79 |
| CD47/SIRPα-blocking agents | Decreased SIRPα signaling | Increased macrophage infiltration and phagocytosis | 87 |
| Increased macrophage production of proinflammatory (antitumoral) cytokines | |||
| Increased macrophage polarization to an M1 phenotype | |||
| Increased ADCC and ADCP |
| Agent . | Molecular mechanism . | Biological impact . | References . |
|---|---|---|---|
| Low-dose radiation | Induction of TLR4, STAT1, ICGR1A, C1q, and APOE in macrophages | Increased macrophage phagocytosis | 26 |
| High-dose radiation | Induction of CD80, CD86, and HLA-DR in macrophages Downregulation of CD163, MRC1, VCAN, and IL-10 Preservation of MMP-2 and MMP-9 activity | Increased macrophage phagocytosis but decreased macrophage production of proinflammatory (antitumoral) cytokines | 25 |
| CTX | Induction of ATF4-mediated paracrine secretion of VEGF-A in lymphoma cells CD47 downregulation | Increased macrophage infiltration and phagocytosis | 28 |
| DOX | Increased tumor immunogenicity Macrophage sparing | Increased macrophage production of proinflammatory (antitumoral) cytokines | 32,33 |
| Vincristine | NLRP3 inflammasome induction Increased production of proinflammatory cytokines (IL-1β, IL-6, and CXCL1) | Increased macrophage production of proinflammatory (antitumoral) cytokines | 34 |
| Bendamustine | Unknown | Unknown | |
| Rituximab | Interaction with macrophage’s FcγRIV, FcγRIII, and FcγRI | Increased ADCC and ADCP | 45,46 |
| Obinutuzumab | Interactions with FcγRIIIa | Increased ADCC and ADCP | 48,51–53 |
| Lenalidomide | Unknown in FL | Unknown in FL | 58,95 |
| BTK inhibitors (ibrutinib) | Downregulation of CXCL12, CXCL13, CCL19, and VEGF Dephosphorylation of ERK1/2, AKT, and PLCγ2 Inhibition of JAK2 | Decreased interaction between protumoral macrophages (M2) and FL cells Increased ADCP | 63,66–68 |
| PI3K inhibitors (idelalisib and duvelisib) | Reduction of BAD phosphorylation via Ser136 Downregulation of BFL-1 Stimulation of NF-κB activation leading to C/EBPβ inactivation | Restored FL dependence on BCL-2 Increased macrophage polarization to an M1 phenotype | 76–79 |
| CD47/SIRPα-blocking agents | Decreased SIRPα signaling | Increased macrophage infiltration and phagocytosis | 87 |
| Increased macrophage production of proinflammatory (antitumoral) cytokines | |||
| Increased macrophage polarization to an M1 phenotype | |||
| Increased ADCC and ADCP |