Diffusion and contrast-enhancement MRI phenotypes associated with immune checkpoint inhibitor exposure and with immune cell infiltration in brain metastases

Francesco Sanvito; Gianluca Nocera; Zexi Wang; Eileen Shiuan; Lu Sun; Sonoko Oshima; Asher Kim; Irina Kryukov; Guowen Shao; Nicholas S Cho; Noriko Salamon; Benjamin M Ellingson; Robert Prins; Won Kim; Jingwen Yao

doi:10.1093/neuonc/noaf084

Diffusion and contrast-enhancement MRI phenotypes associated with immune checkpoint inhibitor exposure and with immune cell infiltration in brain metastases

Neuro Oncol. 2025 Sep 17;27(8):2194-2205. doi: 10.1093/neuonc/noaf084.

Authors

Francesco Sanvito^{1

2}, Gianluca Nocera^{3

4

5

2}, Zexi Wang^{1

2}, Eileen Shiuan^{6

7}, Lu Sun⁷, Sonoko Oshima^{8

1

2}, Asher Kim^{9

1

2}, Irina Kryukov^{1

2}, Guowen Shao^{9

1

2}, Nicholas S Cho^{10

9

1

2}, Noriko Salamon¹, Benjamin M Ellingson^{11

9

6

1

2}, Robert Prins⁶, Won Kim⁶, Jingwen Yao^{9

1

2}

Affiliations

¹ Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
² Brain Tumor Imaging Laboratory (BTIL), Department of Radiological Sciences, University of California Los Angeles, Los Angeles, California, USA.
³ Università Vita-Salute San Raffaele, Milano, Italy.
⁴ Neuroradiology Unit and CERMAC, IRCCS Ospedale San Raffaele, Milano, Italy.
⁵ Department of Neurosurgery and Gamma Knife Radiosurgery, IRCCS Ospedale San Raffaele, Milan, Italy.
⁶ Department of Neurosurgery, Ronald Reagan UCLA Medical Center, University of California Los Angeles, Los Angeles, California, USA.
⁷ Department of Hematology/Oncology, UCLA Medical Center, University of California Los Angeles, Los Angeles, California, USA.
⁸ Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁹ Department of Bioengineering, Henry Samueli School of Engineering and Applied Science, University of California Los Angeles, Los Angeles, California, USA.
¹⁰ Medical Scientist Training Program, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
¹¹ Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

Abstract

Background: MRI-derived apparent diffusion coefficient (ADC) and contrast-enhancement (CE) may represent noninvasive biomarkers to evaluate microstructural tissue changes and histopathological immune cell infiltration induced by immune checkpoint inhibitors (ICI).

Methods: One hundred and twenty-five lesions across 93 patients were analyzed. ADC (reflecting water diffusivity) and CE T1-subtraction maps (reflecting blood-brain barrier permeability) tumor values were used for bivariate histograms of ADC and CE, and to quantify voxel fractions belonging to highADC-highCE and lowADC-lowCE quadrants. The association between ICI exposure and voxel frequency in ADC-CE quadrants was evaluated with multivariate mixed-effects models accounting for corticosteroid exposure and other variables. In a subset of patients (n = 23), the association between immune cell counts (CD45 + cell density) from tissue samples and ADC-CE phenotypes was tested.

Results: ICI and corticosteroid exposure were associated with distinct ADC-CE phenotypes on bivariate histograms. ICI-exposed lesions showed significantly higher voxel frequency in the highADC-highCE quadrant (P < .001) and lower voxel frequency in the lowADC-lowCE quadrant (P < .01), compared to ICI-naïve lesions. Multivariate analyses confirmed that ICI exposure was an independent determinant of higher voxel frequency in the highADC-highCE quadrant (P = .001) and lower voxel frequency in the lowADC-lowCE quadrant (P = .01) in the absence of corticosteroid treatment. Corticosteroid usage significantly influenced the relationship between ADC-CE phenotypes and ICI exposure. Voxel frequency in ADC-CE quadrants was correlated with CD45 + cell density in histopathology (partial ρ = 0.56 P = .01 for highADC-highCE, partial ρ = -0.64 P < .01 for lowADC-lowCE).

Conclusions: ADC-CE phenotypes are associated with ICI exposure and immune cell infiltration in BM, representing potential noninvasive markers to monitor ICI-induced pathophysiological changes.

Keywords: brain metastasis; diffusion imaging; immune checkpoint inhibitors; immunotherapy; magnetic resonance imaging.

MeSH terms

Adult
Aged
Aged, 80 and over
Brain Neoplasms* / diagnostic imaging
Brain Neoplasms* / drug therapy
Brain Neoplasms* / immunology
Brain Neoplasms* / secondary
Contrast Media*
Diffusion Magnetic Resonance Imaging* / methods
Female
Follow-Up Studies
Humans
Immune Checkpoint Inhibitors* / therapeutic use
Magnetic Resonance Imaging* / methods
Male
Middle Aged
Phenotype
Prognosis
Retrospective Studies

Substances

Immune Checkpoint Inhibitors
Contrast Media

Abstract

MeSH terms

Substances

Grants and funding