Repolarized macrophages, induced by intermediate stereotactic dose radiotherapy and immune checkpoint blockade, contribute to long-term survival in glioma-bearing mice

Stessin, A.; Clausi, Mariano Guardia; Zhao, Zirun; Lin, Hong; Hou, Wei; Zhao, Jing; Duong, Timothy Q.; Tsirka, Stella E.; Ryu, Samuel

doi:10.1007/s11060-020-03459-y

Cited by 26 publications

(17 citation statements)

References 20 publications

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“…Promising results were also obtained in mice xenografted with glioblastoma multiforme, whereby anti-PD1 antibody plus a 10 Gy single dose offered significantly better results than a single treatment option alone. In this experiment, radiation triggered macrophages repolarization, increasing M1/M2 ratio [88]. Findings concordant with the former ones were reported by Riva et al that also focused on radiation dosage and fractionation in an attempt to find the more synergistic and effective radio-immunotherapy combinations [89].…”

Section: High Dose Per Fraction Radiotherapy and Immunotherapy: The Most Recent Evidence For A Successful Cooperationsupporting

confidence: 90%

Lattice or Oxygen-Guided Radiotherapy: What If They Converge? Possible Future Directions in the Era of Immunotherapy

Ferini¹,

Valenti²,

Tripoli³

et al. 2021

Cancers

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Palliative radiotherapy has a great role in the treatment of large tumor masses. However, treating a bulky disease could be difficult, especially in critical anatomical areas. In daily clinical practice, short course hypofractionated radiotherapy is delivered in order to control the symptomatic disease. Radiation fields generally encompass the entire tumor mass, which is homogeneously irradiated. Recent technological advances enable delivering a higher radiation dose in small areas within a large mass. This goal, previously achieved thanks to the GRID approach, is now achievable using the newest concept of LATTICE radiotherapy (LT-RT). This kind of treatment allows exploiting various radiation effects, such as bystander and abscopal effects. These events may be enhanced by the concomitant use of immunotherapy, with the latter being ever more successfully delivered in cancer patients. Moreover, a critical issue in the treatment of large masses is the inhomogeneous intratumoral distribution of well-oxygenated and hypo-oxygenated areas. It is well known that hypoxic areas are more resistant to the killing effect of radiation, hence the need to target them with higher aggressive doses. This concept introduces the “oxygen-guided radiation therapy” (OGRT), which means looking for suitable hypoxic markers to implement in PET/CT and Magnetic Resonance Imaging. Future treatment strategies are likely to involve combinations of LT-RT, OGRT, and immunotherapy. In this paper, we review the radiobiological rationale behind a potential benefit of LT-RT and OGRT, and we summarize the results reported in the few clinical trials published so far regarding these issues. Lastly, we suggest what future perspectives may emerge by combining immunotherapy with LT-RT/OGRT.

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Section: High Dose Per Fraction Radiotherapy and Immunotherapy: The Most Recent Evidence For A Successful Cooperationsupporting

confidence: 90%

Lattice or Oxygen-Guided Radiotherapy: What If They Converge? Possible Future Directions in the Era of Immunotherapy

Ferini¹,

Valenti²,

Tripoli³

et al. 2021

Cancers

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“…This combined treatment appears to be highly effective with a 75% complete pathologic response and dramatically improved survival outcomes. Furthermore, CD8+ T-cells and macrophages are necessary for the full effect of the combined therapy, with T lymphocytes playing a role early on and macrophages mediating a later phase of the treatment [ 67 ]. The increased infiltration of anti-tumoral macrophages was associated with a poor radiation response for IDH-wild-type GBM, and the anti-tumoral macrophages correlated with WHO grades and were robustly predicted for the survival performance for GBM patients [ 68 ].…”

Section: Therapeutic Benefitsmentioning

confidence: 99%

Macrophages/Microglia in the Glioblastoma Tumor Microenvironment

Chen

2021

IJMS

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The complex interaction between glioblastoma and its microenvironment has been recognized for decades. Among various immune profiles, the major population is tumor-associated macrophage, with microglia as its localized homolog. The present definition of such myeloid cells is based on a series of cell markers. These good sentinel cells experience significant changes, facilitating glioblastoma development and protecting it from therapeutic treatments. Huge, complicated mechanisms are involved during the overall processes. A lot of effort has been dedicated to crack the mysterious codes in macrophage/microglia recruiting, activating, reprogramming, and functioning. We have made our path. With more and more key factors identified, a lot of new therapeutic methods could be explored to break the ominous loop, to enhance tumor sensitivity to treatments, and to improve the prognosis of glioblastoma patients. However, it might be a synergistic system rather than a series of clear, stepwise events. There are still significant challenges before the light of truth can shine onto the field. Here, we summarize recent advances in this field, reviewing the path we have been on and where we are now.

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“…These results raise the possibility that immune modulation by WBRT may be mediated in part through effects in the non-tumor surrounding tissue, which could implicate resident brain cells such as reactive astrocytes and microglia (14,63). In preclinical glioma models, radiation was used to repolarize macrophages against tumor cells resulting in increased survival (73). In this study, we have not identified which specific cells are producing specific cytokines; however, in future studies single-cell RNA sequencing or single-cell proteomic profiling could be used to clarify the source of these complex immunologic changes in the brain tissue and brain tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Low-Dose Radiation Potentiates the Propagation of Anti-Tumor Immunity against Melanoma Tumor in the Brain after In Situ Vaccination at a Tumor outside the Brain

Clark¹,

Sriramaneni²,

Bates³

et al. 2021

Radiation Research

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Brain metastases develop in over 60% of advanced melanoma patients and negatively impact quality of life and prognosis. In a murine melanoma model, we previously showed that an in situ vaccination (ISV) regimen, combining radiation treatment and intratumoral (IT) injection of immunocytokine (IC: anti-GD2 antibody fused to IL2), along with the immune checkpoint inhibitor anti-CTLA-4, robustly eliminates peripheral flank tumors but only has modest effects on co-occurring intracranial tumors. In this study, we investigated the ability of low-dose radiation to the brain to potentiate anti-tumor immunity against a brain tumor when combined with ISV + anti-CTLA-4. B78 (GD2 + , immunologically ''cold'') melanoma tumor cells were implanted into the flank and the right striatum of the brain in C57BL/6 mice. Flank tumors (50-150 mm 3 ) were treated following a previously optimized ISV regimen [radiation (12 Gy 3 1, treatment day 1), IT-IC (50 lg daily, treatment days 6-10), and anti-CTLA-4 (100 lg, treatment days 3, 6, 9)]. Mice that additionally received whole-brain radiation treatment (WBRT, 4 Gy 3 1) on day 15 demonstrated significantly increased survival compared to animals that received ISV + anti-CTLA-4 alone, WBRT alone or no treatment (control) (P , 0.001, log-rank test). Timing of WBRT was critical, as WBRT administration on day 1 did not significantly enhance survival compared to ISV + anti-CTLA-4, suggesting that the effect of WBRT on survival might be mediated through immune modulation and not just direct tumor cell cytotoxicity. Modest increases in T cells (CD8 + and CD4 + ) and monocytes/macrophages (F4/80 + ) but no changes in FOXP3 + regulatory T cells (Tregs), were observed in brain melanoma tumors with addition of WBRT (on day 15) to ISV + anti-CTLA-4. Cytokine multiplex immunoassay revealed distinct changes in both intracranial melanoma and contralateral normal brain with addition of WBRT (day 15) to ISV + anti-CTLA-4, with notable significant changes in pro-inflammatory (e.g., IFNc, TNFa and LIX/CXCL5) and suppressive (e.g., IL10, IL13) cytokines as well as chemokines (e.g., IP-10/ CXCL10 and MIG/CXCL9). We tested the ability of the alkylphosphocholine analog, NM600, to deliver immunomodulatory radiation to melanoma brain tumors as a targeted radionuclide therapy (TRT). Yttrium-86 ( 86 Y) chelated to NM600 was delivered intravenously by tail vein to mice harboring flank and brain melanoma tumors, and PET imaging demonstrated specific accumulation up to 72 h at each tumor site (;12:1 brain tumor/brain and ;8:1 flank tumor/muscle). When NM600 was chelated to therapeutic b-particle-emitting 90 Y and administered on treatment day 13, T-cell infiltration and cytokine profiles were altered in melanoma brain tumor, like that observed for WBRT. Overall, our results demonstrate that addition of low-dose radiation, timed appropriately with ISV administration to tumors outside the brain, significantly increases survival in animals co-harboring melanoma brain tumors. This observation has potentially important trans...

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Repolarized macrophages, induced by intermediate stereotactic dose radiotherapy and immune checkpoint blockade, contribute to long-term survival in glioma-bearing mice

Cited by 26 publications

References 20 publications

Lattice or Oxygen-Guided Radiotherapy: What If They Converge? Possible Future Directions in the Era of Immunotherapy

Lattice or Oxygen-Guided Radiotherapy: What If They Converge? Possible Future Directions in the Era of Immunotherapy

Macrophages/Microglia in the Glioblastoma Tumor Microenvironment

Low-Dose Radiation Potentiates the Propagation of Anti-Tumor Immunity against Melanoma Tumor in the Brain after In Situ Vaccination at a Tumor outside the Brain

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