Immune evasion

Immune evasion (from Latin evadere = to escape, to escape) is a general term for a process in immunology/pathology in which different pathogens (bacteria, viruses, tumor cells) succeed in evading the biological mechanisms of their recognition or their defense by the adaptive immune system with the aid of specific strategies.

A variety of strategies exist that enable pathogens to evade or subvert the innate or acquired immune response. These include antigenic variation, latency, resistance to immune effector mechanisms, suppression of immune responses. In detail, the strategies of pathogens differ from those of tumor cells, although common mechanisms can also be observed.

Immune evasion strategies in pathogens

• Antigenic variance: One way in which an infectious agent can evade immune surveillance is by altering its antigens. This is particularly important for extracellular pathogens, against which the main defense is the production of antibodies against their surface structures. There are several ways in which such antigenic variations can occur, leading to immune evasion:
• Antigenic drift refers to slow, continuous, and random changes in immunity-forming surface structures (antigens) of pathogenic microorganisms. For example, in influenza viruses, antigenic drift can be caused by point mutations in the genes encoding hemagglutinin and neuraminidase. Such mutations, which occur every 2-3 years, mainly alter the protein segments that are important for the binding of neutralizing antibodies. Thus they escape the immune defence.
• Antigenic shift: Major influenza pandemics are the result of an antigenic shift. This occurs when there is a reassortment of the segmented RNA genome of the influenza virus in an animal host. This can lead to changes in the hemagglutinin protein on the surface of the virus, which is a marker antigen for the organism and against which it had directed its defense strategies. The new virus is poorly or not at all recognised by antibodies and by T cells directed against the previous variant, so that most people are susceptible to the new virus and new infections occur.
• Programmed rearrangements in the DNA of the pathogen (gene rearrangements): The most striking example of a programmed rearrangement is given by trypanosomes. In these, changes in the major surface antigen occur repeatedly within a single infected host. The trypanosome is coated with a single type of glycoprotein, variant-specific glycoprotein (VSG), which elicits a strong antibody response from the host organism. However, the trypanosome genome contains about 1000 VSG genes, each encoding a protein with different antigenic properties. Only one of these is expressed at any time, being placed at an active "expression site" in the genome. The expressed VSG gene can be altered by gene rearrangement, and the VSG protein produced is altered and antigenically undetectable. Trypanosomes thus have an immune system capable of producing many different antibodies by gene rearrangement. They are thus one step ahead of the host organism and its defense strategies.

Other examples of immune evasion include:

• Alteration of the surface antigens of the pathogen to mimic the body's own epitopes(molecular mimicry).
• Alteration of the surface antigens of the pathogen (e.g. herpes viruses) by selective autophagy. This specifically induces the aggregation of important signalling molecules and their degradation. They thus escape the reactions of the innate immune response (Muscolino E et al.2019). Another example of alteration of pathogen surface antigens can be observed in SARS-CoV-2 mutations. SARS-CoV-2 entry is mediated by the spike (S) glycoprotein, which contains the receptor-binding domain (RBD) and the N-terminal domain as the two main targets of neutralizing antibodies. The RBD L452R mutation of SARS-CoV-2 reduces or abolishes the neutralizing activity of 14 of 35 RBD-specific monoclonal antibodies.
• Binding of complement activators: The causative agent of relapsing fever in the Americas, the spirochete Borrelia hermsii, has the ability to reach high pathogen densities in the blood during infection of mammals. Among other things, a surface lipoprotein of B. hermsii (BhCRASP-1 = B. hermsii complement regulator acquiring surface protein 1) is responsible for this, which is able to bind complement regulators and plasminogen from human serum and thus circumvent the body's own immunity.
• Interaction with cytokines or their blockade by appropriate expression of viral or bacterial products.
• Latency mechanisms for permanent residence within cells. An example of this is HIV type 1 (HIV-1) viruses. After infection of the CD4(+) T cells of the immune system, which serve as hosts, the viral RNA is transcribed into DNA by the viral enzyme reverse transcriptase and transported through the pores of the nuclear membrane into the interior of the cell nucleus. There it is preferentially incorporated into certain active genes involved in various cellular functions. When HIV-infected CD4(+) T cells are in a dormant state, the viruses, once incorporated into the cell genome, are immune from attack by antiviral drugs or the immune system. If the T cells are activated, for example, in the context of another infection, they begin to produce copies of the virus in large quantities, which can eventually destroy the host cell and infect new cells. However, some of the viruses remain, in the nucleus of a subpopulation of T cells, the memory CD4(+) T cells, preserved in an inactive state for a long time (Bruna Marini et al.2015).

Immune evasion in malignant tumors:

Many types of human tumors can suppress the immune system to enhance their survival. Some tumor cells escape recognition by the immune system by decreasing the expression of certain antigen-presenting proteins on their surface, thus preventing them from being attacked by cytotoxic T lymphocytes (Meissner M et al. (2005).

Inhibition of immune response by tumor cells: More commonly, however, tumors secrete proteins that inhibit the response of effector T cells and promote the production of regulatory T cells that suppress the immune response (Shevach EM (2004). For melanomas, the immunosuppressive transcriptional repressor ICER has been shown to be a pathway for immune evasion. In the absence of ICER, tumor cells grow more slowly. ICER causes a functional polarization of macrophages, which subsequently adopt a non-inflammatory phenotype. This enables macrophages to induce PD-L1 expression in monocytes, which in turn inhibits cytotoxic T lymphocytes in their anti-tumor efficacy.

Production of an immune-tolerant microenvironment: Certain melanomas can reorganize their stromal microenvironment into structures that mimic immune system lymphoid tissue. They express CCL21, a chemoattractant for various leukocytes and lymphoid tissue inducer(LTi) cells that drive lymphoid neogenesis. This produces an immunotolerant microenvironment that involves the induction of lymphoid-like reticular stromal networks, an altered cytokine milieu, and the recruitment of regulatory leukocyte populations. This sophisticated remodeling recruits and maintains immunoregulatory cells that promote tolerance and tumor progression. In contrast, CCL21-deficient tumors induced antigen-specific immunity (Shields JD et al 2010).

Interferon (IFN)-gamma-induced genes: Colorectal carcinoma cells can apparently increase their pathogenicity by downregulating interferon (IFN)-gamma-induced genes. They thus become resistant to the anti-proliferative and pro-apoptotic effects of IFN-gamma .

1. Bruna Marini et al.(2015) Nuclear architecture dictates HIV-1 integration site selection. Nature doi: 10.1038/nature14226
2. Meissner M et al. (2005) Defects in the human leukocyte antigen class I antigen processing machinery in head and neck squamous cell carcinoma: association with clinical outcome. Clin Cancer Res 11:2552-2560.
3. Muscolino E et al.(2019) Herpesviruses induce aggregation and selective autophagy of host signalling proteins NEMO and RIPK1 as an immune-evasion mechanism. Nature Microbiology DOI: 10.1038/s41564-019-0624-1
4. Shevach EM (2004) Fatal attraction: tumors beckon regulatory T cells. Nat Med 10:900-901.
5. Shields JD et al.(2010) Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Science 328:749-752.