Therapeutic Antibodies at the Intersection of Immune Tolerance and Tumor Immunity: Targeting Dendritic Cells, Tregs, and the Microenvironment

Antibody-Based Modalities in Immunoregulation

Antibody engineering has progressed beyond classical depletion and neutralization strategies to encompass diverse modalities that engage immune tolerance, tissue-specific immunomodulation, and tumor immunity. These new formats include antibody-drug conjugates (ADCs), antibody-antigen fusion proteins, and antibodies designed to target specific immune compartments such as dendritic cells (DCs). The overarching goal is to manipulate the immune response with higher precision, either to suppress autoreactive lymphocytes in autoimmunity or to enhance cytotoxicity against tumor cells in oncology. 

This tolerogenic vs. immunogenic antibody design requires careful selection of targets and mechanisms to align therapeutic intent with immune context. Recent research has increasingly focused on using antibodies to either induce antigen-specific immune tolerance in autoimmune diseases or modulate suppressive immune cell populations in the tumor microenvironment (TME).

In Vivo Targeting of Dendritic Cells for Tolerance Induction

A critical advance in antibody-based immune modulation involves targeting antigens to dendritic cells in vivo to drive tolerance instead of activation. As reviewed by Castenmiller et al. (2021), dendritic cells can be reprogrammed to induce antigen-specific regulatory T cells (Tregs) or tolerize autoreactive T cells when antigen delivery occurs under non-inflammatory conditions. 

This approach relies on delivering disease-relevant antigens directly to DCs via antibodies specific to surface receptors such as: 

• DEC205: An endocytic receptor used extensively in mouse models to induce antigen-specific Tregs when antigens are delivered without adjuvants. 

• DC-SIGN, MR, MGL: C-type lectin receptors that internalize glycosylated antigens and promote tolerogenic phenotypes. 

• Siglecs: Sialic acid-binding immunoglobulin-like lectins that bind to sialylated glycoforms, favoring anti-inflammatory signaling. 

Antigens conjugated to antibodies against these receptors, which are often engineered as antibody-antigen fusion proteins, can induce tolerogenic immune responses, suppressing effector T cell proliferation and promoting IL-10, TGF-β, or retinoic acid-driven Treg development.

Surface Receptors and PRRs on DCs as Therapeutic Gateways

Pattern recognition receptors (PRRs) on dendritic cells are viable entry points for delivering tolerogenic signals. Particularly, C-type lectin receptors such as MR (mannose receptor), DC-SIGN (CD209), MGL, and Langerin are attractive due to their natural role in pathogen recognition and antigen uptake. 

Antibody strategies have explored using: 

• Mannosylated allergens: To target MR and induce IL-10–producing DCs in allergy models. 

• Sialylated antigens: To bind Siglec receptors, which promote tolerogenic signaling cascades and reduce inflammation. 

• Anti-DEC205 fusion constructs: To promote clonal deletion or anergy in autoreactive CD4+ T cells when presented without maturation signals. 

This receptor-targeting strategy is context-sensitive: in the absence of proinflammatory signals, DCs remain immature and instruct tolerance rather than immunity. 

Combining ADCs with Tolerogenic Immune Effects 

Antibody-drug conjugates (ADCs) are traditionally associated with targeted cytotoxicity in oncology. However, their mechanistic framework can be adapted for immune suppression by altering the payload. As discussed by Justiz-Vaillant (2025), ADCs have potential utility in autoimmunity when loaded with apoptosis-inducing or immunomodulatory agents rather than traditional chemotherapeutics. 

In this adapted format, ADCs could: 

• Deliver steroidal payloads (as in ABBV-3373) to inflamed tissues while restricting systemic exposure. 

• Deliver cytokine inhibitors or immunoregulatory small molecules (e.g., JAK inhibitors or calcineurin pathway blockers) specifically to autoreactive immune cells. 

• Be conjugated to IL-10 or TGF-β analogs to promote localized immune deviation without broad immunosuppression. 

Such constructs combine the specificity of antibody targeting with the precision of localized immune modulation. Supporting this approach, preclinical studies in arthritis models have shown that targeting CCR6⁺ effector T cells can suppress inflammation in a highly specific manner. Notably, CCR6 deficiency reduces disease in T cell-dependent models like collagen-induced arthritis but has no impact in innate-driven models. This differential involvement suggests that CCR6-targeted payload delivery could offer selective modulation of adaptive immunity while preserving innate responses.

T Cell Modulation via Tumor and Autoimmune-Linked Targets

Autoimmune diseases and tumors are both characterized by dysregulated T cell responses, which could be either hyperactivation in autoimmunity or functional exhaustion in cancer. Modulating T cells directly or through upstream antigen-presenting cells like DCs provides a convergence point for antibody therapies. 

In autoimmune inflammation (e.g., multiple sclerosis and rheumatoid arthritis), therapeutic strategies include: 

• Inhibiting IL-6, TNF, and GM-CSF. 

• Expanding regulatory T cells (Tregs) via low-dose IL-2 or checkpoint modulation. 

• Delivering disease-relevant antigens in a tolerogenic context (e.g., MOG peptides in MS). 

Conversely, in tumors, checkpoint blockade antibodies (anti-PD-1, anti-CTLA-4) are designed to reverse T cell exhaustion and promote cytotoxic function. The immune pathways are mirror images: tolerance is beneficial in autoimmunity, while activation is needed in cancer. 

A compelling case for precision T cell targeting comes from studies in HLA-B27-associated spondyloarthritis. Expanded CD8⁺ T cell clones expressing TRBV9, identified by conserved TCR β-chain motifs (e.g., CASSVGxSTDTQYF), have been shown to cross-react with both bacterial and self-antigens. These so-called SpA-public clones are enriched in inflamed tissues and are implicated in disease propagation. Targeted depletion of TRBV9⁺ cells using monoclonal antibodies (e.g., Seniprutug) has demonstrated clinical efficacy in ankylosing spondylitis, marking a potential paradigm for antigen-restricted T cell immunotherapy in autoimmunity.

Tumor-Associated Myeloid Cells and Hybrid Cells: The Immunosuppressive Nexus

Tumor-associated myeloid cells, such as M2-polarized macrophages, myeloid-derived suppressor cells (MDSCs), and regulatory DCs, form a major suppressive barrier in solid tumors. These cells secrete IL-10, TGF-β, and IDO, promoting immune tolerance within the TME and impairing cytotoxic T cell function. 

Antibodies that target myeloid checkpoints or reprogram these cells could shift the immune balance toward tumor rejection. Potential strategies include: 

• Anti-CD163 or anti-CD206 antibodies: To deplete or repolarize M2 macrophages. 

• Bispecific antibodies that recognize both tumor antigens (e.g., EpCAM) and myeloid lineage markers (e.g., CD14 or CD11b). 

• Fc-engineered antibodies with enhanced effector function to promote antibody-dependent phagocytosis or cell-mediated cytotoxicity against suppressive myeloid cells. 

One emerging concept is to eliminate hybrid cells, such as CD14+EpCAM+ circulating tumor-macrophage hybrids, which exhibit invasive and immune-evasive characteristics. These hybrid cells may serve as both biomarkers and therapeutic targets. 

Intersection of Tolerance and Tumor Immunity: A Balancing Act

While the goals differ, both tumor and autoimmune immunotherapies engage similar signaling pathways:

The functional role of chemokine receptors like CCR6 further illustrates this context-specificity. In autoimmune disease, CCR6 mediates the recruitment of pathogenic Th17 cells into inflamed tissues. However, in certain tumor environments, CCR6⁺ cells may support immune surveillance or contribute to the formation of tertiary lymphoid structures. Antibodies targeting CCR6 must therefore be evaluated with consideration for immune compartmentalization and disease stage. A subset of tumor-associated dendritic cells (tDCs) has also been identified as metabolically reprogrammed and functionally impaired. These cells exhibit defective antigen presentation and reduced co-stimulatory molecule expression. Antibody-based strategies aiming to restore tDC function, such as CD40 agonists or metabolic modulators, are under investigation as synergistic partners to checkpoint blockade in refractory tumors. 

The disease context determines the optimal antibody design. For instance, a DEC205-targeted fusion protein may promote tolerance in MS but could inhibit effective immunity in cancer. 

Thus, antibody therapeutics require disease-specific tuning of target, payload, and immune context.

Translational Pipeline and Future Directions

Several preclinical and early-stage clinical studies demonstrate the translational potential of these antibody-based strategies: 

• DEC205-antigen fusions are being tested in murine models of autoimmunity, such as MOG-DEC205 in experimental autoimmune encephalomyelitis (EAE). 

• Glyco-conjugated allergens, such as mannosylated ovalbumin, show enhanced tolerance in allergy models. 

• ABBV-3373, an ADC combining anti-TNF antibody with a glucocorticoid receptor modulator, showed improved RA control with reduced systemic steroid burden. 

• CD45-targeted ADCs from Magenta Therapeutics offer conditioning for stem cell transplant with reduced toxicity. 

What remains is the development of: 

• High-throughput screening platforms to evaluate tolerogenic antibody constructs. 

• Biomarkers of DC subset engagement and Treg expansion to monitor responses. 

• Payload innovations that skew immune responses without depleting critical cells.

References: 

1. Xia, W., Zhang, X., Wang, Y., Huang, Z., Guo, X., & Fang, L. (2025). Progress in targeting tumor-associated macrophages in cancer immunotherapy. Frontiers in Immunology, 16, 1658795. https://doi.org/10.3389/fimmu.2025.1658795

2. Justiz-Vaillant, A., & Justiz-Vaillant, A. (2025). Antibody–Drug Conjugates (ADCs) and Their Journey to Autoimmune Disease Immunotherapy. Medical Sciences Forum, 40(1). https://doi.org/10.3390/msf2025040002

3. Castenmiller, C., Van Ree, R., De Jong, E. C., & Van Kooyk, Y. (2021). Tolerogenic Immunotherapy: Targeting DC Surface Receptors to Induce Antigen-Specific Tolerance. Frontiers in Immunology, 12, 643240. https://doi.org/10.3389/fimmu.2021.643240

4. Nan, L., Chen, L., Huang, W., Peng, S., Wang, C., Liao, H., Wang, Y., Cui, Z., Lv, Y., Wang, X., Luo, Y., Tsun, A., Miao, X., & Zhang, J. (2025). Harnessing the innate immune system: A novel bispecific antibody targeting CD47 and CD24 for selective tumor clearance. Journal for Immunotherapy of Cancer, 13(12), e013283. https://doi.org/10.1136/jitc-2025-013283

5. Penkava, F., Sansom, S., & Bowness, P. (2024). Pathogenic T-cell clones in axial spondyloarthritis: What is the evidence? Rheumatology, 63(Supplement_2), ii4-ii6. https://doi.org/10.1093/rheumatology/keae522

6. Bonelli, M., Puchner, A., Göschl, L., Hayer, S., Niederreiter, B., Steiner, G., Tillmann, K., Plasenzotti, R., Podesser, B., Georgel, P., Smolen, J., Scheinecker, C., & Blüml, S. (2018). CCR6 controls autoimmune but not innate immunity-driven experimental arthritis. Journal of cellular and molecular medicine, 22(11), 5278–5285. https://doi.org/10.1111/jcmm.13783