Anti-CD47 antibody–mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response

Tseng, Diane; Volkmer, Jens-Peter; Willingham, Stephen B.; Contreras-Trujillo, Humberto; Fathman, John W.; Fernhoff, Nathaniel B.; Seita, Jun; Inlay, Matthew A.; Weiskopf, Kipp; Miyanishi, Masanori; Weissman, Irving L.

doi:10.1073/pnas.1305569110

Cited by 564 publications

(494 citation statements)

References 34 publications

Supporting

Mentioning

464

Contrasting

Unclassified

Order By: Relevance

“…This suggests that F4/80 ϩ CD80 high and F4/80 ϩ MHC-II high activated macrophages further activate CD4 ϩ T cells and/or induce cytokines, which can provide a biased help to the B cells to induce IgG2c isotype antibodies more effectively. In addition, it was reported that macrophages showed increased phagocytosis of cancer cells in the absence of CD47-mediated signaling (43). Interestingly, SIRP␣-Fc treatment interfering with the CD47 pathway was able to reduce Th2-driven allergic airway inflammation (44), a finding which is in line with the results of IgG2c dominant antibody responses in CD47KO mice after i.n.…”

Section: Discussionsupporting

confidence: 77%

CD47 Plays a Role as a Negative Regulator in Inducing Protective Immune Responses to Vaccination against Influenza Virus

Lee

et al. 2016

J Virol

View full text Add to dashboard Cite

An integrin-associated protein CD47, which is a ligand for the inhibitory receptor signal regulatory protein ␣, is expressed on B and T cells, as well as on most innate immune cells. However, the roles of CD47 in the immune responses to viral infection or vaccination remain unknown. We investigated the role of CD47 in inducing humoral immune responses after intranasal infection with virus or immunization with influenza virus-like particles (VLPs). Virus infection or vaccination with VLPs containing hemagglutinin from A/PR8/34 influenza virus induced higher levels of antigen-specific IgG2c isotype dominant antibodies in CD47-deficient (CD47KO) mice than in wild-type (WT) mice. CD47KO mice with vaccination showed greater protective efficacy against lethal challenge, as evidenced by no loss in body weight and reduced lung viral titers compared to WT mice. In addition, inflammatory responses which include cytokine production, leukocyte infiltrates, and gamma interferon-producing CD4 ؉ T cells, as well as an anti-inflammatory cytokine (interleukin-10), were reduced in the lungs of vaccinated CD47KO mice after challenge with influenza virus. Analysis of lymphocytes indicated that GL7 ؉ germinal center B cells were induced at higher levels in the draining lymph nodes of CD47KO mice compared to those in WT mice. Notably, CD47KO mice exhibited significant increases in the numbers of antigen-specific memory B cells in spleens and plasma cells in bone marrow despite their lower levels of background IgG antibodies. These results suggest that CD47 plays a role as a negative regulator in inducing protective immune responses to influenza vaccination. I nfluenza viruses are common pathogens in the respiratory tract that are highly contagious and can cause pulmonary diseases. Seasonal influenza virus variants annually cause significant levels of morbidity and mortality, mostly in infants, the elderly, and sick people (1, 2). Vaccination is the most effective measure to prevent infections with a variety of pathogens, including influenza virus. Virus-like particles (VLPs) are able to effectively stimulate antigen-presenting cells (APCs), which in turn activate T and B cells (3-6). It has been demonstrated that immunization with influenza VLPs can induce protective humoral responses against seasonal and pandemic influenza virus infections (7-9). However, the mechanisms for evoking long-lasting immune responses are largely unknown.CD47 is a transmembrane protein, which is first identified as integrin ␣v␤3. CD47 that is expressed on hematopoietic and nonhematopoietic cells can interact with an inhibitory receptor signal regulatory protein ␣ (SIRP␣) (10). SIRP␣ is also expressed on dendritic cells (DCs) and macrophages, whereas SIRP␣ is barely expressed on B and T cells (11,12). It has been demonstrated that CD47/CD47 and CD47/SIRP␣ interactions are important for DC and neutrophil migration (13,14). In addition, CD11b ϩ DCs in the lungs express both CD47 and SIRP␣, but CD103 ϩ DCs express only CD47. It was also demonstrated t...

show abstract

Section: Discussionsupporting

confidence: 77%

CD47 Plays a Role as a Negative Regulator in Inducing Protective Immune Responses to Vaccination against Influenza Virus

Lee

et al. 2016

J Virol

View full text Add to dashboard Cite

show abstract

“…are sensitive to blocking anti-CD47 antibodies (233,234,(241)(242)(243)(244)(245)(246)(247)(248)(249)(250). This makes CD47 the first protooncogene that is universally expressed in all cancers; its function is known, and blockade of its function is therapeutic.…”

Section: Cancer Stem Cells and The Therapeutics That Come From Themmentioning

confidence: 99%

“…Mouse macrophages incubated with anti-CD47 antibody, which facilitated phagocytosis of human tumors that express cytoplasmic ova as a tumor antigen, cross-present the ova peptide with MHC I to TCR transgenic CD8, but not CD4 T cells in vitro (247). Such macrophages can be used to vaccinate syngeneic mice that have been transfused with OT-I T cells, and will resist subsequent challenge with a mouse leukemia that expresses cytoplasmic ova.…”

Section: Cancer Stem Cells and The Therapeutics That Come From Themmentioning

confidence: 99%

How One Thing Led to Another

Weissman

2016

Annu. Rev. Immunol.

View full text Add to dashboard Cite

I started research in high school, experimenting on immunological tolerance to transplantation antigens. This led to studies of the thymus as the site of maturation of T cells, which led to the discovery, isolation, and clinical transplantation of purified hematopoietic stem cells (HSCs). The induction of immune tolerance with HSCs has led to isolation of other tissue-specific stem cells for regenerative medicine. Our studies of circulating competing germline stem cells in colonial protochordates led us to document competing HSCs. In human acute myelogenous leukemia we showed that all preleukemic mutations occur in HSCs, and determined their order; the final mutations occur in a multipotent progenitor derived from the preleukemic HSC clone. With these, we discovered that CD47 is an upregulated gene in all human cancers and is a “don't eat me” signal; blocking it with antibodies leads to cancer cell phagocytosis. CD47 is the first known gene common to all cancers and is a target for cancer immunotherapy.

show abstract

“…For example, blocking of the colony stimulating factor 1 receptor (CSF-1R) in mice with aggressive mammary cancer, reduces pulmonary metastases regulated by macrophages ( Figure 1 ). An alternative approach to this is stimulating macrophages to increase T cell immune response [8] (Tseng et al, 2013). This was done using anti-CD47 antibody, which increased phagocytosis of cancer cells by macrophages and increased priming of CD8 + T cells, accompanied by decreased priming of CD4 + T cells.…”

Section: Macrophages As Drug Targetsmentioning

confidence: 99%