Anti-CTLA-4 Antibodies of IgG2a Isotype Enhance Antitumor Activity through Reduction of Intratumoral Regulatory T Cells

The therapeutic potential of CTLA-4 blockade is evident in the ability of anti-CTLA-4 antibody to induce regression of established tumors. In an elegant set of experiments using a panel of murine immunoglobulin in various isotypes, Selby and colleagues delineated the mechanism of action of CTLA-4 blockade. Anti-CTLA-4 promotes antitumor activity by a selective reduction of intratumoral T-regulatory cells along with concomitant activation of T-effector cells. Antitumor activity of CTLA-4 antibody blockade is thought to be mediated by interfering with the negative regulation of T-effector cell (Teff) function resulting from CTLA-4 engagement by B7-ligands. In addition, a role for CTLA-4 on regulatory T cells (Treg), wherein CTLA-4 loss or inhibition results in reduced Treg function, may also contribute to antitumor responses by anti-CTLA-4 treatment. We have examined the role of the immunoglobulin constant region on the antitumor activity of anti-CTLA-4 to analyze in greater detail the mechanism of action of anti-CTLA-4 antibodies. Anti-CTLA-4 antibody containing the murine immunoglobulin G (IgG)2a constant region exhibits enhanced antitumor activity in subcutaneous established MC38 and CT26 colon adenocarcinoma tumor models compared with anti-CTLA-4 containing the IgG2b constant region. Interestingly, anti-CTLA-4 antibodies containing mouse IgG1 or a mutated mouse IgG1-D265A, which eliminates binding to all Fcγ receptors (FcγR), do not show antitumor activity in these models. Assessment of Teff and Treg populations at the tumor and in the periphery showed that anti-CTLA-4-IgG2a mediated a rapid and dramatic reduction of Tregs at the tumor site, whereas treatment with each of the isotypes expanded Tregs in the periphery. Expansion of CD8+ Teffs is observed with both the IgG2a and IgG2b anti-CTLA-4 isotypes, resulting in a superior Teff to Treg ratio for the IgG2a isotype. These data suggest that anti-CTLA-4 promotes antitumor activity by a selective reduction of intratumoral Tregs along with concomitant activation of Teffs. Cancer Immunol Res; 1(1); 32–42. ©2013 AACR.

• Publication year

  2013

• Venue

  Cancer immunology research

• Publication date

  2013-04-07

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1158/2326-6066.CIR-13-0013PMID 24777248
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma.

  2013cited by this paper
• Cutting Edge: CTLA-4 on Effector T Cells Inhibits In Trans

  2012cited by this paper
• An immune-active tumor microenvironment favors clinical response to ipilimumab

  2012cited by this paper
• IL-10 directly activates and expands tumor-resident CD8(+) T cells without de novo infiltration from secondary lymphoid organs.

  2012cited by this paper
• Properties of mouse and human IgG receptors and their contribution to disease models.

  2012cited by this paper
• Cutting Edge: Cell-Extrinsic Immune Regulation by CTLA-4 Expressed on Conventional T Cells

  2012cited by this paper
• Cutting Edge: FcγRIII (CD16) and FcγRI (CD64) Are Responsible for Anti-Glycoprotein 75 Monoclonal Antibody TA99 Therapy for Experimental Metastatic B16 Melanoma

  2012cited by this paper
• IL-1α and IL-1β Recruit Different Myeloid Cells and Promote Different Stages of Sterile Inflammation

  2011cited by this paper
• A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma

  2011cited by this paper
• Trans-Endocytosis of CD80 and CD86: A Molecular Basis for the Cell-Extrinsic Function of CTLA-4

  2011cited by this paper
• IL-10 elicits IFNγ-dependent tumor immune surveillance.

  2011cited by this paper
• Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab

  2011cited by this paper
• Anti-CTLA4 monoclonal antibodies: the past and the future in clinical application

  2011cited by this paper
• Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy.

  2010cited by this paper
• Two Distinct Mechanisms of Augmented Antitumor Activity by Modulation of Immunostimulatory/Inhibitory Signals

  2010cited by this paper
• Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting

  2010cited by this paper
• Improved survival with ipilimumab in patients with metastatic melanoma.

  2010cited by this paper
• Phase I/II trial of tremelimumab in patients with metastatic melanoma.

  2009cited by this paper
• Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti–CTLA-4 antibodies

  2009cited by this paper
• Intratumoral Immune Cell Infiltrates, FoxP3, and Indoleamine 2,3-Dioxygenase in Patients with Melanoma Undergoing CTLA4 Blockade

  2009cited by this paper
• Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses.

  2009cited by this paper
• CD28 and CTLA‐4 coreceptor expression and signal transduction

  2009cited by this paper
• CTLA-4 Control over Foxp3+ Regulatory T Cell Function

  2008cited by this paper
• CTLA-4 blockade increases IFNγ-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients

  2008cited by this paper
• Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients

  2008cited by this paper
• Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation

  2008cited by this paper
• Cell intrinsic mechanisms of T‐cell inhibition and application to cancer therapy

  2008cited by this paper
• Potential conflicts of interest

  2007cited by this paper
• Tremelimumab (CP-675,206), a cytotoxic T lymphocyte associated antigen 4 blocking monoclonal antibody in clinical development for patients with cancer.

  2007cited by this paper
• CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells.

  2006influential reference
• Response to Comment on “Analysis of the Cellular Mechanism of Antitumor Responses and Autoimmunity in Patients Treated with CTLA-4 Blockade”

  2006cited by this paper
• Divergent Immunoglobulin G Subclass Activity Through Selective Fc Receptor Binding

  2005cited by this paper
• Analysis of the Cellular Mechanism of Antitumor Responses and Autoimmunity in Patients Treated with CTLA-4 Blockade

  2005cited by this paper
• Activity and Safety of CTLA-4 Blockade Combined with Vaccines in Cynomolgus Macaques

  2003cited by this paper
• Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets

  2000cited by this paper
• Cytotoxic T Lymphocyte–Associated Antigen 4 Plays an Essential Role in the Function of Cd25+Cd4+ Regulatory Cells That Control Intestinal Inflammation

  2000cited by this paper
• Engagement of Cytotoxic T Lymphocyte–associated Antigen 4 (CTLA-4) Induces Transforming Growth Factor β (TGF-β) Production by Murine CD4+ T Cells

  1998cited by this paper
• Fc receptors are required in passive and active immunity to melanoma.

  1998cited by this paper
• CTLA-4 ligation delivers a unique signal to resting human CD4 T cells that inhibits interleukin-2 secretion but allows Bcl-X(L) induction.

  1998cited by this paper
• Cutting Edge: CTLA-4 Ligation Delivers a Unique Signal to Resting Human CD4 T Cells That Inhibits Interleukin-2 Secretion but Allows Bcl-XL Induction

  1998cited by this paper
• High-affinity binding of the neonatal Fc receptor to its IgG ligand requires receptor immobilization.

  1997cited by this paper
• Specific blockade of CTLA-4/B7 interactions results in exacerbated clinical and histologic disease in an actively-induced model of experimental allergic encephalomyelitis.

  1997cited by this paper
• CTLA-4 blockade enhances clinical disease and cytokine production during experimental allergic encephalomyelitis.

  1996cited by this paper
• Enhancement of Antitumor Immunity by CTLA-4 Blockade

  1996cited by this paper
• A melanosomal membrane protein is a cell surface target for melanoma therapy.

  1996cited by this paper
• CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation

  1995cited by this paper
• CTLA-4 can function as a negative regulator of T cell activation.

  1994cited by this paper
• Multiple differences between the nucleic acid sequences of the IgG2aa and IgG2ab alleles of the mouse.

  1981cited by this paper

• Tumor microenvironment in bone sarcomas: Implications for immunotherapy and emerging therapeutic vulnerabilities (Review)

  2026influential citation
• ROSE12, a novel anti-CTLA-4 FcγRs binding-enhanced antibody activated by extracellular adenosine triphosphate, shows tumor-selective regulatory T-cell depletion and antitumor efficacy without systemic immune activation

  2026cites this paper
• Modified Shenlingbaizhu decoction suppresses colon cancer via enhancing memory-like Tfh differentiation and B cell responses.

  2026cites this paper
• Regulatory T cells in renal cell carcinoma: tumor-promoting mechanisms and emerging therapeutic strategies.

  2025cites this paper
• Regulatory T Cell Depletion in Cancer: Challenges, Opportunities, and Future Directions for Antibody Development.

  2025cites this paper
• Leveraging the Tumor Microenvironment as a Target for Cancer Therapeutics: A Review of Emerging Opportunities

  2025cites this paper
• Engineered ipilimumab variants that bind human and mouse CTLA-4

  2025cites this paper
• Intra-Tumoral Treg Ablation Unleashes NK Cell-Mediated Control of CD8 T Cell-Resistant Tumors

  2025cites this paper
• Treatment Decision-Making in Unresectable Hepatocellular Carcinoma: Importance of Understanding the Different Response Patterns between IO plus Anti-VEGF and IO plus IO Regimens

  2025cites this paper
• Immunometabolism of Tregs: mechanisms, adaptability, and therapeutic implications in diseases

  2025cites this paper
• Targeted inhibition of Aurora kinase A promotes immune checkpoint inhibition efficacy in human papillomavirus-driven cancers

  2025cites this paper
• Dual roles and therapeutic targeting of tumor-associated macrophages in tumor microenvironments

  2025cites this paper
• Association between antibody-dependent cellular cytotoxicity activity of antitumor antibodies and infusion reactions: a pharmacovigilance analysis using the Japanese adverse drug event report database

  2025cites this paper
• Non-redundant immune checkpoints direct therapeutic resistance to chemoimmunotherapy in pancreatic ductal adenocarcinoma.

  2025cites this paper
• Immunosuppressive JAG2+ tumor‐associated neutrophils hamper PD‐1 blockade response in ovarian cancer by mediating the differentiation of effector regulatory T cells

  2025cites this paper
• Bispecific targeting of 4-1BB and CCR8 boosts antitumor immunity via Ti-Treg depletion and CD8+ activation

  2025cites this paper
• Nanobody-based bispecific antibody engagers targeting CTLA-4 or PD-L1 for cancer immunotherapy

  2025cites this paper
• Microenvironmental regulation of solid tumour resistance to CAR T cell therapy

  2025cites this paper
• Antibody-dependent cellular cytotoxicity of anti-programmed death-ligand 1 antibodies for T cells attenuate their antitumor efficacy in a murine tumor model.

  2025cites this paper
• A multi-omics analysis of effector and resting treg cells in pan-cancer

  2025cites this paper
• Immunogenomic classification and nomogram development and validation for colorectal cancer survival prediction based on immune-related genes

  2025cites this paper
• High Antigenicity for Treg Cells Confers Resistance to PD‐1 Blockade Therapy via High PD‐1 Expression in Treg Cells

  2025cites this paper
• Leveraging T cells for cancer immunotherapy

  2025cites this paper
• Immunomodulation of UVB-induced regulatory T cells prevents the establishment of squamous cell carcinoma

  2025influential citation
• Radiation therapy causes a STING and MyD88-independent upregulation of CD80 and CD86 in macrophages and monocytes that limits tumor control

  2025cites this paper
• Regulatory T cells in homeostasis and disease: molecular mechanisms and therapeutic potential

  2025cites this paper
• Anti-CTLA-4 Treatment Abrogates Co-stimulation Blockade-induced Acceptance of Transgenic Porcine Islets in Humanized Mice

  2025cites this paper
• The immunological heterogeneity of squamous cell carcinoma and adenocarcinoma of the uterine cervix: a systematic review

  2025cites this paper
• Lanatoside C activates the E3 ligase STUB1 to inhibit FOXP3 transcriptional activity and promote antitumor immunity

  2025influential citation
• Cationic Peptide Conjugation Enhances Intratumoral Retention and Antitumor Efficacy of Immune Checkpoint Blockade Antibodies.

  2025cites this paper
• Impact of tumor localization on antitumor immunity with conditionally activated CTLA-4 blockade

  2025cites this paper
• pH-dependent dissociation from CTLA-4 in early endosomes improves both safety and antitumor activity of anti-CTLA-4 antibodies

  2025cites this paper
• CTLA-4—two pathways to anti-tumour immunity?

  2025cites this paper
• Tumor microenvironment: recent advances in understanding and its role in modulating cancer therapies

  2025cites this paper
• Fc-optimized anti-CTLA-4 antibodies increase tumor-associated high endothelial venules and sensitize refractory tumors to PD-1 blockade

  2025cites this paper
• Effects of COVID-19 vaccination on irAEs and prognosis in lung cancer patients receive PD-(L)1 inhibitors

  2025cites this paper
• ImmunoPET imaging of c-Met using a nanobody-based tracer [68Ga]Ga-NOTA-PFCM01 in pancreatic ductal adenocarcinoma models and non-human primates

  2025cites this paper
• Ectopic ULBP2 Is Associated with Decreased NKG2D Expression in CD8+ T Cells Under T Cell-Modulatory Conditions in a Murine Tumor Model

  2025cites this paper
• Depletion of Effector Regulatory T Cells Associates with Major Response to Induction Dual Immune Checkpoint Blockade

  2025cites this paper
• Synergistic Effect of Thermoneutral Housing and Chronotherapeutic PD-1 Blockade Overcomes Melanoma Resistance

  2025cites this paper
• ADCC: the rock band led by therapeutic antibodies, tumor and immune cells

  2025cites this paper
• Immunotherapy and the Tumor Microenvironment in Brain Metastases from Non-Small Cell Lung Cancer: Challenges and Future Directions

  2025cites this paper
• A novel designed anti-PD-L1/OX40 bispecific antibody augments both peripheral and tumor-associated immune responses for boosting anti-tumor immunity.

  2024cites this paper
• Fc Effector Function of Immune Checkpoint Blocking Antibodies in Oncology

  2024cites this paper
• LAG‐3—An incompletely understood target in cancer therapy

  2024cites this paper
• Immune Checkpoint Inhibitors: Fundamental Mechanisms, Current Status and Future Directions

  2024cites this paper
• Integrated Analysis of Single-Cell and Bulk RNA-Sequencing Based on EcoTyper Machine Learning Framework Identifies Cell-State-Specific M2 Macrophage Markers Associated with Gastric Cancer Prognosis

  2024cites this paper
• Depletion of conventional CD4+ T cells is required for robust priming and dissemination of tumor antigen-specific CD8+ T cells in the setting of anti-CD4 therapy

  2024cites this paper
• A combined radio-immunotherapy regimen eradicates late-stage tumors in mice

  2024cites this paper
• Fc-enhanced anti-CTLA-4 depletes tumor-infiltrating regulatory T cells to augment immune effects of androgen ablation in high-risk prostate cancer

  2024cites this paper
• Comparing neoantigen cancer vaccines and immune checkpoint therapy unveils an effective vaccine and anti-TREM2 macrophage-targeting dual therapy

  2024cites this paper
• A Case of Bullous Pemphigoid with Significant Infiltration of CD4-Positive T Cells during Treatment with Pembrolizumab, Accompanied by Pembrolizumab-Induced Multi-Organ Dysfunction

  2024cites this paper
• Lymphocyte T Subsets and Outcome of Immune Checkpoint Inhibitors in Melanoma Patients: An Oncologist’s Perspective on Current Knowledge

  2024cites this paper
• Fc gamma receptors: Their evolution, genomic architecture, genetic variation, and impact on human disease

  2024cites this paper
• Spatial multiplex analysis of lung cancer reveals that regulatory T cells attenuate KRAS-G12C inhibitor–induced immune responses

  2024cites this paper
• Review of T Helper 2-Type Inflammatory Diseases Following Immune Checkpoint Inhibitor Treatment

  2024cites this paper
• Bi-specific antibody engagers for cancer immunotherapy

  2024cites this paper
• Immunotherapy for colorectal cancer

  2024cites this paper
• Anti-CTLA4 treatment reduces lymphedema risk potentially through a systemic expansion of the FOXP3+ Treg population

  2024cites this paper
• Study on Molecular Mechanism of AGGF1 Neutralizing Antibody Combined with Anti CTLA-4 Antibody in Suppressing the Growth of Mouse Melanoma

  2024cites this paper
• Botensilimab, an Fc-Enhanced Anti–CTLA-4 Antibody, Is Effective against Tumors Poorly Responsive to Conventional Immunotherapy

  2024cites this paper
• Immune checkpoint inhibition of metastatic melanoma: achieving high efficacy in the face of high toxicity

  2024cites this paper
• Fc-optimized checkpoint antibodies for cancer immunotherapy.

  2024cites this paper
• Selective depletion of tumor-infiltrating regulatory T cells with BAY 3375968, a novel Fc-optimized anti-CCR8 antibody

  2024cites this paper
• Spectrum of Treg and self-reactive T cells: single cell perspectives from old friend HTLV-1

  2024cites this paper
• Combining toll-like receptor agonists with immune checkpoint blockade affects antitumor vaccine efficacy

  2024cites this paper
• Targeting the dendritic cell-secreted immunoregulatory cytokine CCL22 alleviates radioresistance.

  2024cites this paper
• Current and Future Trends of Colorectal Cancer Treatment: Exploring Advances in Immunotherapy

  2024cites this paper
• The enhanced antitumor activity of bispecific antibody targeting PD-1/PD-L1 signaling

  2024cites this paper
• ICOS costimulation in combination with CTLA-4 blockade remodels tumor-associated macrophages toward an antitumor phenotype

  2024cites this paper
• The Combination of Anti-CD47 Antibody with CTLA4 Blockade Enhances Anti-Tumor Immunity in Non-Small Cell Lung Cancer via Normalization of Tumor Vasculature and Reprogramming of the Immune Microenvironment

  2024cites this paper
• Manipulating regulatory T cells: is it the key to unlocking effective immunotherapy for pancreatic ductal adenocarcinoma?

  2024cites this paper
• Post-immunotherapy CTLA-4 Ig treatment improves antitumor efficacy

  2024cites this paper
• Current state of immune checkpoints therapy for glioblastoma

  2024cites this paper
• Immune checkpoint expression patterns on T cell subsets in light-chain amyloidosis: VISTA, PD-1, and TIGIT as potential therapeutic targets

  2024cites this paper
• Evaluation of regulatory T-cells in cancer immunotherapy: therapeutic relevance of immune checkpoint inhibition

  2024cites this paper
• A new target of radiotherapy combined with immunotherapy: regulatory T cells

  2024cites this paper
• Anti-CTLA-4 nanobody as a promising approach in cancer immunotherapy

  2024cites this paper
• Immunotherapy of microsatellite stable colorectal cancer: resistance mechanisms and treatment strategies.

  2024cites this paper
• Recombinant Newcastle disease viruses expressing immunological checkpoint inhibitors induce a pro-inflammatory state and enhance tumor-specific immune responses in two murine models of cancer

  2024cites this paper
• Immune regulation and the tumor microenvironment in anti-PD-1/PDL-1 and anti-CTLA-4 therapies for cancer immune evasion: A bibliometric analysis

  2024cites this paper
• The Nephrotoxicity of Checkpoint Inhibitors: A Mini Review

  2024cites this paper
• The application of antibody-based agents in cancer therapy based on their mechanisms of action

  2024cites this paper
• Fc-silent anti-TIGIT antibodies potentiate anti-tumor immunity without depleting regulatory T cells.

  2024cites this paper
• CAR-T Cell Therapy in Pancreatic and Biliary Tract Cancers: An Updated Review of Clinical Trials

  2024cites this paper
• TIGIT predominantly regulates the immune response via regulatory T cells

  2024cites this paper
• Microbiota-dependent activation of CD4+ T cells induces CTLA-4 blockade–associated colitis via Fcγ receptors

  2024cites this paper
• The breast cancer tumor microenvironment and precision medicine: immunogenicity and conditions favoring response to immunotherapy

  2024cites this paper
• Tumor Microenvironment Regulates Immune Checkpoints: Emerging Need of Combinatorial Therapies

  2024cites this paper
• Targeting cytotoxic lymphocyte antigen 4 (CTLA-4) in breast cancer

  2024cites this paper
• The B7:CD28 family and friends: Unraveling coinhibitory interactions.

  2024cites this paper
• Both intratumoral regulatory T cell depletion and CTLA-4 antagonism are required for maximum efficacy of anti-CTLA-4 antibodies

  2023cites this paper
• Incidence of Hyper Progressive Disease in Combination Immunotherapy and Anti-Programmed Cell Death Protein 1/Programmed Death-Ligand 1 Monotherapy for Unresectable Hepatocellular Carcinoma

  2023cites this paper
• CXCR3 expression in regulatory T cells drives interactions with type I dendritic cells in tumors to restrict CD8+ T cell antitumor immunity.

  2023cites this paper
• Immune-related adverse events of immune checkpoint inhibitors: a review

  2023cites this paper
• Exosomes-delivered PD-L1 siRNA and CTLA-4 siRNA protect against growth and tumor immune escape in colorectal cancer.

  2023cites this paper
• New developments in the mechanism and application of immune checkpoint inhibitors in cancer therapy (Review)

  2023cites this paper
• TIGIT is a key inhibitory checkpoint receptor in lymphoma

  2023cites this paper
• Interruption of the Intratumor CD8:Treg Crosstalk Improves the Efficacy of PD-1 Immunotherapy

  2023cites this paper
• Targeting Histone 3 Variants Epigenetic Landscape and Inhibitory Immune Checkpoints: An Option for Paediatric Brain Tumours Therapy

  2023cites this paper