scholarly journals Preclinical and clinical development of therapeutic antibodies targeting functions of CD47 in the tumor microenvironment

2020 ◽  
Vol 3 (3) ◽  
pp. 179-192
Author(s):  
Sukhbir Kaur ◽  
Kyle V Cicalese ◽  
Rajdeep Banerjee ◽  
David D Roberts
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Cytotoxic T Cells ◽  
Regulatory Protein ◽  
Immune Surveillance ◽  
Hematologic Malignancies ◽  
Clinical Development ◽  
Surface Glycoprotein ◽  
Cell Surface Glycoprotein ◽  
Thrombospondin 1

ABSTRACT CD47 is a ubiquitously expressed cell surface glycoprotein that functions as a signaling receptor for thrombospondin-1 and as the counter-receptor for signal regulatory protein-α (SIRPα). Engaging SIRPα on macrophages inhibits phagocytosis, and CD47 thereby serves as a physiological marker of self. However, elevated CD47 expression on some cancer cells also protects tumors from innate immune surveillance and limits adaptive antitumor immunity via inhibitory SIRPα signaling in antigen-presenting cells. CD47 also mediates inhibitory thrombospondin-1 signaling in vascular cells, T cells, and NK cells, and blocking inhibitory CD47 signaling on cytotoxic T cells directly increases tumor cell killing. Therefore, CD47 functions as an innate and adaptive immune checkpoint. These findings have led to the development of antibodies and other therapeutic approaches to block CD47 functions in the tumor microenvironment. Preclinical studies in mice demonstrated that blocking CD47 can limit the growth of hematologic malignancies and solid tumors and enhance the efficacy of conventional chemotherapy, radiation therapy, and some targeted cancer therapies. Humanized CD47 antibodies are showing promise in early clinical trials, but side effects related to enhanced phagocytic clearance of circulating blood cells remain a concern. Approaches to circumvent these include antibody preloading strategies and development of antibodies that recognize tumor-specific epitopes of CD47, SIRPα antibodies, and bivalent antibodies that restrict CD47 blockade to specific tumor cells. Preclinical and clinical development of antibodies and related biologics that inhibit CD47/SIRPα signaling are reviewed, including strategies to combine these agents with various conventional and targeted therapeutics to improve patient outcome for various cancers.

scholarly journals Hyaluronate-CD44 Interactions Can Induce Murine B-Cell Activation

Blood ◽  
1997 ◽  
Vol 89 (8) ◽  
pp. 2901-2908 ◽  
Author(s):  
Asimah Rafi ◽  
Mitzi Nagarkatti ◽  
Prakash S. Nagarkatti
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Critical Role ◽  
Surface Glycoprotein ◽  
B Cell Differentiation ◽  
B Cell Activation ◽  
Cell Surface Glycoprotein ◽  
Immunodeficient Mice

Abstract CD44 is a widely distributed cell surface glycoprotein whose principal ligand has been identified as hyaluronic acid (HA), a major component of the extracellular matrix (ECM). Recent studies have demonstrated that activation through CD44 leads to induction of effector function in T cells and macrophages. In the current study, we investigated whether HA or monoclonal antibodies (MoAbs) against CD44 would induce a proliferative response in mouse lymphocytes. Spleen cells from normal and nude, but not severe combined immunodeficient mice, exhibited strong proliferative responsiveness to stimulation with soluble HA or anti-CD44 MoAbs. Furthermore, purified B cells, but not T cells, were found to respond to HA. HA was unable to stimulate T cells even in the presence of antigen presenting cells (APC) and was unable to act as a costimulus in the presence of mitogenic or submitogenic concentrations of anti-CD3 MoAbs. In contrast, stimulation of B cells with HA in vitro, led to B-cell differentiation as measured by production of IgM antibodies in addition to increased expression of CD44 and decreased levels of CD45R. The fact that the B cells were responding directly to HA through its binding to CD44 and not to any contaminants or endotoxins was demonstrated by the fact that F(ab)2 fragments of anti-CD44 MoAbs or soluble CD44 fusion proteins could significantly inhibit the HA-induced proliferation of B cells. Also, HA-induced proliferation of B cells was not affected by the addition of polymixin B, and B cells from lipopolysaccharide (LPS)-unresponsive C3H/HeJ strain responded strongly to stimulation with HA. Furthermore, HA, but not chondroitin-sulfate, another major component of the ECM, induced B-cell activation. It was also noted that injection of HA intraperitoneally, triggered splenic B cell proliferation in vivo. Together, the current study demonstrates that interaction between HA and CD44 can regulate murine B-cell effector functions and that such interactions may play a critical role during normal or autoimmune responsiveness of B cells.

scholarly journals Tumor microenvironment in triple-negative breast cancer: the correlation of tumor-associated macrophages and tumor-infiltrating lymphocytes

2021 ◽  
Author(s):  
H. Kuroda ◽  
T. Jamiyan ◽  
R. Yamaguchi ◽  
A. Kakumoto ◽  
A. Abe ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cytotoxic T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Tumor Associated Macrophages ◽  
Free Survival ◽  
Infiltrating Lymphocytes

Abstract Purpose Immune cells such as cytotoxic T cells, helper T cells, B cells or tumor-associated macrophages (TAMs) contribute to the anti-tumor response or pro-tumorigenic effect in triple negative breast cancer (TNBC). The interrelation of TAMs, T and B tumor-infiltrating lymphocytes (TILs) in TNBC has not been fully elucidated. Methods We evaluated the association of tumor-associated macrophages, T and B TILs in TNBC. Results TNBCs with a high CD68+, CD163+ TAMs and low CD4+, CD8+, CD20+ TILs had a significantly shorter relapse-free survival (RFS) and overall survival (OS) than those with low CD68+, CD163+ TAMs and high CD4+, CD8+, CD20+ TILs. TNBCs with high CD68+ TAMs/low CD8+ TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD68+ TAMs/high CD8+ TILs, low CD68+ TAMs/high CD8+ TILs, and low CD68+/low CD8+. TNBCs with high CD163+ TAMs/low CD8+, low CD20 + TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD163+ TAMs/high CD8+ TILs and high CD163+ TAMs /high CD20+ TILs. Conclusions Our study suggests that TAMs further create an optimal tumor microenvironment (TME) for growth and invasion of cancer cells when evasion of immunoreactions due to T and B TILs occurs. In TNBCs, all these events combine to affect prognosis. The process of TME is highly complex in TNBCs and for an improved understanding, larger validation studies are necessary to confirm these findings.

scholarly journals Dendritic cell targeting with Fc-enhanced CD40 antibody agonists induces durable antitumor immunity in humanized mouse models of bladder cancer

2021 ◽  
Vol 13 (594) ◽  
pp. eabd1346
Author(s):  
Christopher S. Garris ◽  
Jeffrey L. Wong ◽  
Jeffrey V. Ravetch ◽  
David A. Knorr
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Mouse Models ◽  
Antitumor Immunity ◽  
Bladder Tumor ◽  
Immune Surveillance ◽  
Disease Recurrence ◽  
Bcg Therapy ◽  
Agonist Antibody

Intravesical immunotherapy using Bacille Calmette-Guérin (BCG) attenuated bacteria delivered transurethrally to the bladder has been the standard of care for patients with high-risk non–muscle-invasive bladder cancer (NMIBC) for several decades. BCG therapy continues to be limited by high rates of disease recurrence and progression, and patients with BCG-unresponsive disease have few effective salvage therapy options besides radical cystectomy, highlighting a need for new therapies. We report that the immune-stimulatory receptor CD40 is highly expressed on dendritic cells (DCs) within the bladder tumor microenvironment of orthotopic bladder cancer mouse models, recapitulating CD40 expression by DCs found in human disease. We demonstrate that local CD40 agonism in mice with orthotopic bladder cancer through intravesical delivery of anti-CD40 agonist antibodies drives potent antitumor immunity and induces pharmacodynamic effects in the bladder tumor microenvironment, including a reduction in CD8+ T cells with an exhausted phenotype. We further show that type 1 conventional DCs (cDC1) and CD8+ T cells are required for both bladder cancer immune surveillance and anti-CD40 agonist antibody responses. Using orthotopic murine models humanized for CD40 and Fcγ receptors, we demonstrate that intravesical treatment with a fully human, Fc-enhanced anti-CD40 agonist antibody (2141-V11) induces robust antitumor activity in both treatment-naïve and treatment-refractory settings, driving long-term systemic antitumor immunity with no evidence of systemic toxicity. These findings support targeting CD40-expressing DCs in the bladder cancer microenvironment through an intravesical agonistic antibody approach for the treatment of NMIBC.

Thyroid status regulates tumor microenvironment delineating breast cancer fate

2021 ◽  
Author(s):  
Helena Andrea Sterle ◽  
Ximena Hildebrandt ◽  
Matías Valenzuela Álvarez ◽  
María Alejandra Paulazo ◽  
Luciana Mariel Gutierrez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Lung Metastasis ◽  
Cytotoxic T Cells ◽  
Suppressor Cells ◽  
Thyroid Status ◽  
Cd8 Cells ◽  
Regulatory T Lymphocytes ◽  
Starting Point

The patient’s hormonal context plays a crucial role in the outcome of cancer. However, the association between thyroid disease and breast cancer risk remains unclear. We evaluated the effect of thyroid status on breast cancer growth and dissemination in an immunocompetent mouse model. For this, hyperthyroid and hypothyroid Balb/c mice were orthotopically inoculated with triple negative breast cancer 4T1 cells. Tumors from hyperthyroid mice showed increased growth rate and an immunosuppressive tumor microenvironment, characterized by increased IL-10 levels and decreased percentage of activated cytotoxic T cells. On the other hand, a delayed tumor growth in hypothyroid animals was associated with increased tumor infiltration of activated CD8+ cells and a high IFNγ/IL-10 ratio. Paradoxically, hypothyroid mice developed a higher number of lung metastasis than hyperthyroid animals. This was related to an increased secretion of tumor CCL2 and an immunosuppressive systemic environment, with increased proportion of regulatory T cells and IL-10 levels in spleens. A lower number of lung metastasis in hyperthyroid mice was related to the reduced presence of mesenchymal stem cells in tumors and metastatic sites. These animals also exhibited decreased percentages of regulatory T lymphocytes and myeloid-derived suppressor cells in spleens, but increased activated CD8+ cells and IFNγ/IL-10 ratio. Therefore, thyroid hormones modulate the cellular and cytokine content of the breast tumor microenvironment. The better understanding of the mechanisms involved in these effects could be a starting point for the discovery of new therapeutic targets for breast cancer.

scholarly journals CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation.

1995 ◽  
Vol 182 (2) ◽  
pp. 459-465 ◽  
Author(s):  
M F Krummel ◽  
J P Allison
Keyword(s):  
T Cells ◽  
T Cell ◽  
Costimulatory Molecule ◽  
Surface Glycoprotein ◽  
T Cell Proliferation ◽  
Cell Surface Glycoprotein ◽  
Costimulatory Signals ◽  
Low Levels ◽  
Opposing Effects ◽  
Antigen Presenting

The importance of the B7/CD28/CTLA-4 molecules has been established in studies of antigen-presenting cell-derived B7 and its interaction with the T cell costimulatory molecule CD28. CTLA-4, a T cell surface glycoprotein that is related to CD28, can also interact with B7-1 and B7-2. However, less is known about the function of CTLA-4, which is expressed at highest levels after activation. We have generated an antibody to CTLA-4 to investigate the consequences of engagement of this molecule in a carefully defined system using highly purified T cells. We show here that the presence of low levels of B7-2 on freshly explanted T cells can partially inhibit T cell proliferation, and this inhibition is mediated by interactions with CTLA-4. Cross-linking of CTLA-4 together with the TCR and CD28 strongly inhibits proliferation and IL-2 secretion by T cells. Finally, results show that CD28 and CTLA-4 deliver opposing signals that appear to be integrated by the T cell in determining the response to activation. These data strongly suggest that the outcome of T cell antigen receptor stimulation is regulated by CD28 costimulatory signals, as well as inhibitory signals derived from CTLA-4.

scholarly journals Mechanism- and Immune Landscape-Based Ranking of Therapeutic Responsiveness of 22 Major Human Cancers to Next Generation Anti-CTLA-4 Antibodies

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 284
Author(s):  
Peng Zhang ◽  
Xinxin Xiong ◽  
Christian Rolfo ◽  
Xuexiang Du ◽  
Yan Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
Clinical Development ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Cancer Types ◽  
New Generation

Background: CTLA-4 was the first immune checkpoint targeted for cancer therapy and the first target validated by the FDA (Food and Drug Administration) after approval of the anti-CTLA-4 antibody, Ipilimumab. However, clinical response rates to anti-CTLA-4 antibodies are lower while the rates of immunotherapy-related adverse events (irAE) are higher than with anti-PD-1 antibodies. As a result, the effort to target CTLA-4 for cancer immunotherapy has stagnated. To reinvigorate CTLA-4-targeted immunotherapy, we and others have reported that rather than blocking CTLA-4 interaction with its cognate targets, CD80 and CD86, anti-CTLA-4 antibodies achieve their therapeutic responses through selective depletion of regulatory T cells in the tumor microenvironment. Accordingly, we have developed a new generation of anti-CTLA-4 antibodies with reduced irAE and enhanced antibody-dependent cell-mediated cytotoxicity/phagocytosis (ADCC/ADCP). A major unresolved issue is how to select appropriate cancer types for future clinical development. Methods: We generated a landscape of the immune tumor microenvironment from RNAseq and genomic data of 7279 independent cancer samples belonging to 22 cancer types from The Cancer Genomics Atlas (TCGA) database. Based primarily on genomic and RNAseq data from pre-treatment clinical samples of melanoma patients who were later identified as responders and nonresponders to the anti-CTLA-4 antibody Ipilimumab, we identified 5 ranking components of responsiveness to anti-CTLA-4, including CTLA-4 gene expression, ADCC potential, mutation burden, as well as gene enrichment and cellular composition that favor CTLA-4 responsiveness. The total ranking number was calculated by the sum of 5 independent partitioning values, each comprised of 1–3 components. Results: Our analyses predict metastatic melanoma as the most responsive cancer, as expected. Surprisingly, non-small cell lung carcinoma (NSCLC) is predicted to be highly responsive to anti-CTLA-4 antibodies. Single-cell RNAseq analysis and flow cytometry of human NSCLC-infiltrating T cells supports the potential of anti-CTLA-4 antibodies to selectively deplete intratumoral Treg. Conclusions: Our in silico and experimental analyses suggest that non-small cell lung carcinoma will likely respond to a new generation of anti-CTLA-4 monoclonal antibodies. Our approach provides an objective ranking of the sensitivity of human cancers to anti-CTLA-4 antibodies. The comprehensive ranking of major cancer types provides a roadmap for clinical development of the next generation of anti-CTLA-4 antibodies.

scholarly journals Cholangiocarcinoma with respect to IgG4 Reaction

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Kenichi Harada ◽  
Yasuni Nakanuma
Keyword(s):  
T Cells ◽  
Plasma Cells ◽  
Cytotoxic T Cells ◽  
Immune Surveillance ◽  
Intraepithelial Neoplasia ◽  
Cell Switching ◽  
Igg4 Related Disease ◽  
Regulatory Cytokine ◽  
High Risk Factor ◽  
Antigen Presenting

IgG4 reactions marked by infiltration of IgG4-positive plasma cells in affected organs occur in cancer patients and in patients with IgG4-related diseases. Extrahepatic cholangiocarcinomas including gall bladder cancer are often accompanied by significant IgG4 reactions; these reactions show a negative correlation with CD8-positive cytotoxic T cells, suggesting that the evasion of immune surveillance is associated with cytotoxic T cells. The regulatory cytokine IL-10 may induce IgG4-positive plasma cell differentiation or promote B cell switching to IgG4 in the presence of IL-4. Cholangiocarcinoma cells may function as nonprofessional antigen presenting cells that indirectly induce IgG4 reactions via the IL-10-producing cells and/or these may act as Foxp3-positive and IL-10-producing cells that directly induce IgG4 reactions. Moreover, IgG4-related disease is a high-risk factor for cancer development; IgG4-related sclerosing cholangitis (IgG4-SC) cases associated with cholangiocarcinoma or its precursor lesion biliary intraepithelial neoplasia (BilIN) have been reported. IgG4-positive cell infiltration is an important finding of IgG4-SC but is not a histological hallmark of IgG4-SC. For the diagnosis of IgG4-SC, its differentiation from cholangiocarcinoma remains important.

scholarly journals Antiangiogenic antibody BD0801 combined with immune checkpoint inhibitors achieves synergistic antitumor activity and affects the tumor microenvironment

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Liting Xue ◽  
Xingyuan Gao ◽  
Haoyu Zhang ◽  
Jianxing Tang ◽  
Qian Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Clinical Development ◽  
Cell Mediated Immunity ◽  
Tumor Models ◽  
Anti Vegf

Abstract Background Signaling through VEGF/VEGFR induces cancer angiogenesis and affects immune cells. An increasing number of studies have recently focused on combining anti-VEGF/VEGFR agents and immune checkpoint inhibitors (ICIs) to treat cancer in preclinical and clinical settings. BD0801 is a humanized rabbit anti-VEGF monoclonal antibody in the clinical development stage. Methods In this study, the anti-cancer activities of BD0801 and its potential synergistic anti-tumor effects when combined with different immunotherapies were assessed by using in vitro assays and in vivo tumor models. Ex vivo studies were conducted to reveal the possible mechanisms of actions (MOA) underlying the tumor microenvironment modification. Results BD0801 showed more potent antitumor activity than bevacizumab, reflected by stronger blockade of VEGF/VEGFR binding and enhanced inhibitory effects on human umbilical vein endothelial cells (HUVECs). BD0801 exhibited dose-dependent tumor growth inhibitory activities in xenograft and murine syngeneic tumor models. Notably, combining BD0801 with either anti-PD-1 or anti-PD-L1 antibodies showed synergistic antitumor efficacy in both lung and colorectal cancer mouse models. Furthermore, the mechanistic studies suggested that the MOA of the antitumor synergy involves improved tumor vasculature normalization and enhanced T-cell mediated immunity, including increased tumor infiltration of CD8+ and CD4+ T cells and reduced double-positive CD8+PD-1+ T cells. Conclusions These data provide a solid rationale for combining antiangiogenic agents with immunotherapy for cancer treatment and support further clinical development of BD0801 in combination with ICIs.

Pembrolizumab treatment increases chemotaxis of cytotoxic T cells in head and neck cancer patients within the adenosine‐rich tumor microenvironment

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Hannah S. Newton ◽  
Ameet A. Chimote ◽  
Vaibhavkumar S. Gawali ◽  
Sarah Palackdharry ◽  
David Hildeman ◽  
...  
Keyword(s):  
T Cells ◽  
Head And Neck Cancer ◽  
Tumor Microenvironment ◽  
Head And Neck ◽  
Cancer Patients ◽  
Neck Cancer ◽  
Cytotoxic T Cells

Rag1 Deficiency Does Not Affect Myelodysplasia but Leads to More Rapid Leukemic Transformation in a Mouse Model of MDS.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2784-2784
Author(s):  
Sheryl M Gough ◽  
Yang Jo Chung ◽  
Peter D. Aplan
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Peripheral Blood ◽  
Cytotoxic T Cells ◽  
Immune Surveillance ◽  
Severe Anemia ◽  
Control Groups ◽  
Leukemic Transformation ◽  
Significant Difference

Abstract Abstract 2784 Poster Board II-760 MDS comprises a premalignant heterogeneous group of clonal stem cell disorders that also show bone marrow dysplasia and which often evolve to acute myeloid leukemia (AML). Aplastic anemia (AA) patients also share the bone marrow failure, anemia and resulting peripheral blood cytopenias of MDS. AA is thought to be caused by an oligoclonal expansion of cytotoxic T-cells that target haematopoietic stem and progenitor cells. The severe anemia and leucopenia characteristic of both diseases is relieved in AA patients and some MDS patients by immunosuppressive therapy, supporting the role of cytotoxic T-cells in the etiology of AA. However, the role of the lymphocytes in progressive MDS remains unclear. MDS has been associated with a number of genetic aberrations, including chromosomal translocations involving the NUP98 gene. Using mice that express a NUP98-HOXD13 (NHD13) transgene, previously shown to manifest the same clinical symptoms as those of MDS patients, we have followed a cohort of NHD13/Rag1−/− mice to determine if the absence of lymphocytes, especially T cells, might 1) diminish the severity of the MDS, or 2) effect transformation and/or survival in the NHD13 mice, as would be predicted by an “immune surveillance” hypothesis of malignant transformation. Serial CBCs at two month time intervals were used to evaluate the extent of anemia and leucopenia in NHD13+ /Rag1+/+ and NHD13/Rag1−/−, as well as WT/Rag1+/− and WT/Rag1−/− control groups over a 15 month period. NHD13/Rag1−/− mice were generated by crossing the NHD13+ (C57BL/6) with the B6;129S7-Rag1tm1Mom/J mouse, and housed in a Specific Pathogen-Free (SPF) environment. Mice were euthanized and analyzed when CBCs indicated severe anemia/leucopenia or leukemic transformation, or when determined to be unwell (hunched, immobile, dyspnea) by observation. Flow cytometry, histology and genomic analyses further determined leukemia subtype, extent of infiltration and leukemia clonality. NHD13+ /Rag1+/+ and NHD13/Rag1−/− mice showed no significant differences at any two month time-point in hemoglobin (Hg), mean corpuscular volume (MCV), or platelet levels, and progressive MDS occurred in both groups. Consistent with previous studies, and excluding cases that showed evident transformation to acute leukemia, NHD13+ /Rag1+/+ mice showed low WBC, neutrophil and lymphocyte numbers, which were not significantly different from the NHD13/Rag1−/− mice. NHD13/Rag1−/− mice did however show a significantly reduced survival when compared with the NHD13+ /Rag1+/+ mice (Log-rank test, p = 0.0135), and survival medians of 11 and 13 months, respectively. Incidence of leukemic transformation was increased in the NHD13/Rag1−/− compared with the NHD13+ /Rag1+/+ mice (p=0.0079). A range of leukemia subtypes was observed in both the NHD13+ /Rag1+/+ and NHD13/Rag1−/− mice, including myeloid, B-cell, T-cell, and erythroid leukemias. In the SPF environment provided, the WT/Rag1+/− and WT/Rag1−/− control groups showed no significant difference in survival rates. Serial CBC data indicated that there was no significant difference in the timing or degree of peripheral blood cytopenias between the NHD13+ /Rag1+/+ and NHD13/Rag1−/− mice, supporting the conclusion that absence of lymphocytes does not lead to improvement in the peripheral blood cytopenias caused by the NHD13 transgene. This observation suggests that the NHD13 transgene does not produce MDS caused by an autoimmune phenomenon. The poorer survival and increased frequency of leukemic transformation in the NHD13/Rag1−/− mice suggests that lymphocytes might play a role in the evolution of MDS to AML in the NHD13 mouse model, and supports the ‘immune surveillance' hypothesis. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document