CD47-SIRPα Checkpoint Disruption in Metastases Requires Tumor-Targeting Antibody for Molecular and Engineered Macrophage Therapies.

The macrophage checkpoint interaction CD47-SIRPα is an emerging target for cancer therapy, but clinical trials of monoclonal anti-CD47 show efficacy only in liquid tumors when combined with tumor-opsonizing IgG. Here, in challenging metastatic solid tumors, CD47 deletion shows no effect on tumor growth unless combined with otherwise ineffective tumor-opsonization, and we likewise show wild-type metastases are suppressed by SIRPα-blocked macrophages plus tumor-opsonization. Lung tumor nodules of syngeneic B16F10 melanoma cells with CD47 deletion show opsonization drives macrophage phagocytosis of B16F10s, consistent with growth versus phagocytosis calculus for exponential suppression of cancer. Wild-type CD47 levels on metastases in lungs of immunocompetent mice and on human metastases in livers of immunodeficient mice show that systemic injection of antibody-engineered macrophages also suppresses growth. Such in vivo functionality can be modulated by particle pre-loading of the macrophages. Thus, even though CD47-SIRPα disruption and tumor-opsonizing IgG are separately ineffective against established metastatic solid tumors, their combination in molecular and cellular therapies prolongs survival.

Psychometric testing of the Fall Risks for Older People in the Community screening tool (FROP-Com screen) for community-dwelling people with stroke.

OBJECTIVE: The Falls Risk for Older People in the Community assessment (FROP-Com) was originally developed using 13 risk factors to identify the fall risks of community-dwelling older people. To suit the practical use in busy clinical settings, a brief version adopting 3 most fall predictive risk factors from the original FROP-Com, including the number of falls in the past 12 months, assistance required to perform domestic activities of daily living and observation of balance, was developed for screening purpose (FROP-Com screen). The objectives of this study were to investigate the inter-rater and test-retest reliability, concurrent and convergent validity, and minimum detectable change of the FROP-Com screen in community-dwelling people with stroke. PARTICIPANTS: Community-dwelling people with stroke (n = 48) were recruited from a local self-help group, and community-dwelling older people (n = 40) were recruited as control subjects. RESULTS: The FROP-Com screen exhibited moderate inter-rater (Intraclass correlation coefficient [ICC]2,1 = 0.79, 95% confidence interval [CI]: 0.65-0.87) and test-retest reliability (ICC3,1 = 0.70, 95% CI: 0.46-0.83) and weak associations with two balance measures, the Berg Balance Scale (BBS) (rho = -0.38, p = 0.008) and the Timed "Up & Go" (TUG) test (rho = 0.35, p = 0.016). The screen also exhibited a moderate association with the Chinese version of the Activities-specific Balance Confidence Scale (ABC-C) (ABC-C; rho = -0.65, p<0.001), a measure of subjective balance confidence. CONCLUSIONS: The FROP-Com screen is a reliable clinical tool with convergent validity paralleled with subjective balance confidence measure that can be used in fall risk screening of community-dwelling people with stroke. However, one individual item, the observation of balance, will require additional refinement to improve the potential measurement error.

Macrophages show higher levels of engulfment after disruption of cis interactions between CD47 and the checkpoint receptor SIRPα.

The macrophage checkpoint receptor SIRPα signals against phagocytosis by binding CD47 expressed on all cells - including macrophages. Here, we found that inhibiting cis interactions between SIRPα and CD47 on the same macrophage increased engulfment ('eating') by approximately the same level as inhibiting trans interactions. Antibody blockade of CD47, as pursued in clinical trials against cancer, was applied separately to human-derived macrophages and to red blood cell (RBC) targets for phagocytosis, and both scenarios produced surprisingly similar increases in RBC engulfment. Blockade of both macrophages and targets resulted in hyper-phagocytosis, and knockdown of macrophage-CD47 likewise increased engulfment of 'foreign' cells and particles, decreased the baseline inhibitory signaling of SIRPα, and linearly increased binding of soluble CD47 in trans, consistent with cis-trans competition. Many cell types express both SIRPα and CD47, including mouse melanoma B16 cells, and CRISPR-mediated deletions modulate B16 phagocytosis, consistent with cis-trans competition. Additionally, soluble SIRPα binding to human CD47 displayed on Chinese hamster ovary (CHO) cells was suppressed by SIRPα co-display, and atomistic computations confirm SIRPα bends and binds CD47 in cis Safety and efficacy profiles for CD47-SIRPα blockade might therefore reflect a disruption of both cis and trans interactions.