Microbes as Master Immunomodulators: Immunopathology, Cancer and Personalized Immunotherapies

Abstract

The intricate interplay between the immune system and microbes is an essential part of the physiological homeostasis in health and disease. Immunological recognition of commensal microbes, such as bacterial species resident in the gut or lung as well as dormant viral species, i.e., cytomegalovirus (CMV) or Epstein-Barr virus (EBV), in combination with a balanced immune regulation, is central to achieve immune-protection. Emerging evidence suggests that immune responses primed to guard against commensal microbes may cause unexpected pathological outcomes, e.g., chronic inflammation and/or malignant transformation. Furthermore, translocation of immune cells from one anatomical compartment to another, i.e., the gut-lung axis via the lymphatics or blood has been identified as an important factor in perpetrating systemic inflammation, tissue destruction, as well as modulating host-protective immune responses. We present in this review immune response patterns to pathogenic as well as non-pathogenic microbes and how these immune-recognition profiles affect local immune responses or malignant transformation. We discuss personalized immunological therapies which, directly or indirectly, target host biological pathways modulated by antimicrobial immune responses.

Keywords: antibodies; cancer; immune responses; immunotherapy; inflammation; microbiota; neoplasia; pathogens.

FIGURE 1

Targeted immunotherapeutic strategies against infection- and inflammation-induced neoplasia. The schematic shows some of the possible strategies which can be pursued in developing targeted host-directed immunotherapies based on biomarkers in infection-induced inflammation and oncogenesis. Cells infected with viruses or bacteria may induce physiological and anatomical changes in tissue, leading to reduced barrier functions and tissue integrity. This contributes to the overall local immunological milieu associated with the production of pro-inflammatory cytokines, as IL-6, IL-18, IL-12, and GM-CSF. In some cases of viral infection, VEGF production is also observed, which leads to neovascularization and poses a risk for malignant transformation. The same is true for EGF release by host cells in some bacterial infections. The ensuing T-cell activation culminates in production of IFN-γ, TNF-α, IL-2 as well as IL-17 in several infections – which can be pathogenic and contribute to chronic inflammation and neoplasia. To the right of the schematic are dysplastic cells, which can present antigenic epitopes to T cells, some of which may be protective (HLA class I-restricted pathogen- or host cell-derived structures), while others may exacerbate the IL-17 response (HLA class-II-restricted Th17 epitopes). Excess IL-17 as well as IL-6 can be neutralized using therapeutic antibodies which are clinically licensed. VEGF neutralization, as well as EGFR blockade, may be clinically useful in halting disease progression due to aberrant inflammation induced by infection. Hydralazine and valproic acid, both of which are clinically approved medications, can increase HLA class I expression in host cells, thereby augmenting and enhancing CD8+ T cell-mediated immune control. FAK inhibitors may be able to increase MICA/B expression in neoplastic cells (as well dysplastic ones) to improve immune surveillance by TCR Vγ9Vδ2 T cells and NK cells expressing the killer receptor NKG2D. Virus-induced T-cell responses against certain host-cell epitopes may educate T cells to subsequently recognize tumor cells; such T-cell populations may be used in active cell therapies and the nominal (antigen-specific) TCR may be utilized for transfer into recipient surrogate immune cells. Host cell surface molecules associated with malignant transformation induced by infection and inflammation, if recognized by circulating as well as tissue-associated antibodies, may be used as as templates for inducing ADCC as well as viable targets for biologically and clinically relevant chimeric antigen receptors (CARs) transgenically expressed by immune effector cells.