Epitope spreading

The principle was described in 1992 by Lehmann, Forsthuber, Miller, and Sercarz. Initially, the authors demonstrated in a model of experimental autoimmune encephalomyelitis that a T-cell response initially directed against a dominant epitope can expand over the course of the disease to include additional, previously cryptic epitopes of the same autoantigen. The term was initially called “determinant spreading”; the term “epitope spreading,” which is commonly used today, became established primarily through the work of Stephen D. Miller and Christine L. Vanderlugt beginning in 1995–1996.

The term "epitope spreading" (also known, in a broader sense, as antigen spreading ) refers to the expansion of the B- or T-cell response that occurs during the course of an immune reaction, from an antigenically prominent initial epitope to one (or more) additional, structurally distinct, non-cross-reactive epitopes.

Epitope spreading is thus not primarily based on a cross-reaction of an antibody or T-cell receptor with analogous molecular structures. Rather, during the course of an autochthonous or artificially induced inflammatory reaction, new epitopes—which are molecularly and immunologically distinct—are released and recognized as additional antigenic target structures. Thus, epitope expansion differs from molecular mimicry, in which structural similarities between a foreign antigen and a self-antigen lead to cross-reactivity.

In general, the following distinctions can be made:

• Intramolecular epitope expansion: The immune response extends to additional epitopes of the same antigen.
• Intermolecular epitope spreading: The immune response additionally targets epitopes of other antigens, which are often spatially or functionally associated.

The following immunological scenario can be assumed: 

• A spontaneous or therapy-induced immune response initially targets a specific tumor epitope.
• Cytotoxic T cells destroy the recognized tumor cells.
• As the cells disintegrate, additional tumor antigens and neoantigens are released.
• Dendritic cells take up these antigens and present previously unrecognized epitopes via MHC-I and MHC-II molecules.
• This activates additional CD8⁺ and CD4⁺ T-cell clones, as well as B cells if present.
• The immune response gradually broadens and targets multiple antigenic structures of the tumor.

The process begins with an initially limited inflammatory immune response against an immunologically dominant and molecularly defined epitope. In the process, additional antigens are released, processed, and presented by antigen-presenting cells. These inflammatory reactions may cause profound tissue transformations. As a result, epitopes that were previously unrecognized or only inadequately recognized—some of which are cryptic—can become immunologically relevant. Due to their antigenic potency, new lymphocyte clones are activated. The tissue damage triggered by autoimmune inflammation can lead to:

• the release of additional, previously hidden, or immunologically inaccessible autoantigens, and consequently, an expansion of the autoimmune reaction—originally directed against a primary antigen—to include another autoantigen that was previously irrelevant.
• Uptake and processing of these antigens by antigen-presenting cells,
• presentation of new antigen structures via MHC molecules,
• activation of additional autoreactive T- and B-cell clones,
• and the successive expansion of the autoantibody and T-cell repertoires.

The following molecular mechanisms are conceivable:

• Intramolecular epitope spreading: expansion of the immune response to additional epitopes of the same tumor antigen
• Intermolecular epitope spreading: Expansion of the immune response to epitopes of other tumor antigens
• Neoantigen spreading
  • Neoantigen spreading: Expansion of the immune response to new, mutation-induced, tumor-specific neoepitopes
  • Neoantigen spreading: Expansion of the immune response to previously cryptic, tumor-specific neoepitopes uncovered by autochthonous or artificially induced inflammation (using novel mRNA vaccine strategies based on non-tumor-specific antigens (e.g., using sequences derived from pathogens or of synthetic origin), immunologically “cold” tumors can be transformed into inflamed, treatment-responsive microenvironments (Magoola M et al. 2025).

Altered humoral or cellular responses are also possible:

• Humoral epitope expansion: broadening of the autoantibody spectrum through the recruitment of new B-cell clones
• T-cell epitope expansion: Expansion of the autoreactive T-cell response to additional peptide-MHC complexes

Autoimmune diseases: The phenomenon of epitope spreading plays a major role in the onset, chronicity, and clinical progression of autoimmune diseases. It helps explain both chronic disease courses and unexpected phenotypic shifts (Cornaby C et al. 2014).

Cancer: Epitope spreading can be triggered or amplified by immune checkpoint inhibitors, tumor vaccines based on patient-specific tumor sequencing, novel mRNA vaccine strategies, oncolytic viruses, or chemotherapy and radiation therapy—provided these treatments induce immunogenic tumor cell death.

The phenomenon of epitope spreading has been described in conditions such as multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, rheumatoid arthritis, autoimmune bullous dermatoses, and in oncology. 

Epitope spreading in bullous autoimmune diseases: 

In bullous pemphigoid, the immune response is initially often directed against the immunodominant NC16A domain of BP180/collagen XVII. As the disease progresses, additional epitopes within BP180 may be recognized—intramolecular epitope spreading—and additional reactivity against BP230 may develop.

Similar processes have been described in pemphigus disorders. For example, the transition from pemphigus vulgaris to pemphigus foliaceus involves a shift or overlap from DSG3 to DSG1 antibodies(see Daneshpazhooh M 2020). Immunological follow-up tests usually showed a marked decline in the original antibody profiles. However, other studies showed an unchanged immunological profile despite a changed phenotype (Futei Y et al. 2000/Ohyama B et al. 2012).

Epitope spreading in oncology:

Epitope spreading is primarily a desirable mechanism for enhancing antitumor immunity:

• It broadens the immune response against a heterogeneous tumor.
• It can target tumor cell clones that have lost the original target antigen.
• It hinders immunological escape via antigen loss.
• It can promote systemic and longer-lasting immune responses, including immune memory.
• It may explain why immunotherapy directed against a single antigen ultimately elicits a broader tumor response.

Clinical example: The success of cancer immunotherapies is based on the targeted attack of highly expressed neoepitopes, which primarily favors tumors with a high mutation burden. Tumor resistance to an initially effective immunotherapy may be due to a blockade of the damage response. This can be restored by enhancing early type I interferon responses. This, in turn, enables epitopic spread and a self-amplifying response in treatment-resistant tumors (Qdaisat S et al. 2025).

mRNA vaccine strategies: Using novel mRNA vaccine strategies based on non-tumor-specific antigens (e.g., sequences derived from pathogens or of synthetic origin), immunologically “cold” tumors can be transformed into inflamed, treatment-responsive microenvironments. Unlike conventional approaches, which require patient-specific tumor sequencing and production times of 8 to 12 weeks, this platform uses pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) to trigger broad activation of the innate immune system via multiple pattern recognition receptors (PRRs). The central therapeutic mechanism is epitope expansion, in which vaccine-induced inflammation exposes previously hidden tumor antigens, allowing the immune system to mount responses against tumor-specific targets without having previously recognized these antigens. These vaccines, administered via optimized lipid nanoparticles (LNPs) or alternative polymer-based systems, induce epitope expansion, enhance the response to checkpoint inhibitors, and establish a durable antitumor memory (Qdaisat S et al. 2025; Magoola M et al. 2025)

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