B Cells in the Gastrointestinal Tumor Microenvironment with a Focus on Pancreatic Cancer: Opportunities for Precision Medicine?

We review state-of-the-art in translational and clinical studies focusing on the tumor microenvironment (TME) with a focus on tumor-infiltrating B cells (TIBs). The TME is a dynamic matrix of mutations, immune-regulatory networks, and distinct cell-to-cell interactions which collectively impact on disease progress. We discuss relevant findings concerning B cells in pancreatic cancer, the concepts of "bystander" B cells, the role of antigen-specific B cells contributing to augmenting anticancer-directed immune responses, the role of B cells as prognostic markers for response to checkpoint inhibitors (ICBs), and the potential use in adoptive cell tumor-infiltrating lymphocyte (TIL) products.

Neoepitope targets of tumour-infiltrating lymphocytes from patients with pancreatic cancer.

BACKGROUND: Pancreatic cancer exhibits a poor prognosis and often presents with metastasis at diagnosis. Immunotherapeutic approaches targeting private cancer mutations (neoantigens) are a clinically viable option to improve clinical outcomes. METHODS: 3/40 TIL lines (PanTT26, PanTT39, PanTT77) were more closely examined for neoantigen recognition. Whole-exome sequencing was performed to identify non-synonymous somatic mutations. Mutant peptides were synthesised and assessed for antigen-specific IFN-γ production and specific tumour killing in a standard Cr51 assay. TIL phenotype was tested by flow cytometry. Lymphocytes and HLA molecules in tumour tissue were visualised by immunohistochemistry. RESULTS: PanTT26 and PanTT39 TILs recognised and killed the autologous tumour cells. PanTT26 TIL recognised the KRASG12v mutation, while a PanTT39 CD4+ TIL clone recognised the neoepitope (GLLRYWRTERLF) from an aquaporin 1-like protein (gene: K7N7A8). Repeated stimulation of TILs with the autologous tumour cells line lead to focused recognition of several mutated targets, based on IFN-γ production. TILs and corresponding PBMCs from PanTT77 showed shared as well as mutually exclusively tumour epitope recognition (TIL-responsive or PBMC-responsive). CONCLUSION: This study provides methods to robustly screen T-cell targets for pancreatic cancer. Pancreatic cancer is immunogenic and immunotherapeutic approaches can be used to develop improved, targeted therapies.

Precision medicine in the clinical management of respiratory tract infections including multidrug-resistant tuberculosis: learning from innovations in immuno-oncology.

PURPOSE OF REVIEW: In the light of poor management outcomes of antibiotic-resistant respiratory tract infection (RTI)-associated sepsis syndrome and multidrug-resistant tuberculosis (MDR-TB), new management interventions based on host-directed therapies (HDTs) are warranted to improve morbidity, mortality and long-term functional outcomes. We review developments in potential HDTs based on precision cancer therapy concepts applicable to RTIs including MDR-TB. RECENT FINDINGS: Immune reactivity, tissue destruction and repair processes identified during studies of cancer immunotherapy share common pathogenetic mechanisms with RTI-associated sepsis syndrome and MDR-TB. T-cell receptors (TCRs) and chimeric antigen receptors targeting pathogen-specific or host-derived mutated molecules (major histocompatibility class-dependent/ major histocompatibility class-independent) can be engineered for recognition by TCR γδ and natural killer (NK) cells. T-cell subsets and, more recently, NK cells are shown to be host-protective. These cells can also be activated by immune checkpoint inhibitor (ICI) or derived from allogeneic sources and serve as potential for improving clinical outcomes in RTIs and MDR-TB. SUMMARY: Recent developments of immunotherapy in cancer reveal common pathways in immune reactivity, tissue destruction and repair. RTIs-related sepsis syndrome exhibits mixed immune reactions, making cytokine or ICI therapy guided by robust biomarker analyses, viable treatment options.

Clinically Relevant Immune Responses against Cytomegalovirus: Implications for Precision Medicine.

Immune responses to human cytomegalovirus (CMV) can be used to assess immune fitness in an individual. Further to its clinical significance in posttransplantation settings, emerging clinical and translational studies provide examples of immune correlates of protection pertaining to anti-CMV immune responses in the context of cancer or infectious diseases, e.g., tuberculosis. In this viewpoint, we provide a brief overview about CMV-directed immune reactivity and immune fitness in a clinical context and incorporate some of our own findings obtained from peripheral blood or tumour-infiltrating lymphocytes (TIL) from patients with advanced cancer. Observations in patients with solid cancers whose lesions contain both CMV and tumour antigen-specific T-cell subsets are highlighted, due to a possible CMV-associated "bystander" effect in amplifying local inflammation and subsequent tumour rejection. The role of tumour-associated antibodies recognising diverse CMV-derived epitopes is also discussed in light of anti-cancer immune responses. We discuss here the use of anti-CMV immune responses as a theranostic tool-combining immunodiagnostics with a personalised therapeutic potential-to improve treatment outcomes in oncological indications.

The impact of inflationary cytomegalovirus-specific memory T cells on anti-tumour immune responses in patients with cancer.

Human cytomegalovirus (CMV) is a ubiquitous, persistent beta herpesvirus. CMV infection contributes to the accumulation of functional antigen-specific CD8+ T-cell pools with an effector-memory phenotype and enrichment of these immune cells in peripheral organs. We review here this 'memory T-cell inflation' phenomenon and associated factors including age and sex. 'Collateral damage' due to CMV-directed immune reactivity may occur in later stages of life - arising from CMV-specific immune responses that were beneficial in earlier life. CMV may be considered an age-dependent immunomodulator and a double-edged sword in editing anti-tumour immune responses. Emerging evidence suggests that CMV is highly prevalent in patients with a variety of cancers, particularly glioblastoma. A better understanding of CMV-associated immune responses and its implications for immune senescence, especially in patients with cancer, may aid in the design of more clinically relevant and tailored, personalized treatment regimens. 'Memory T-cell inflation' could be applied in vaccine development strategies to enrich for immune reactivity where long-term immunological memory is needed, e.g. in long-term immune memory formation directed against transformed cells.

Epstein-Barr virus- and cytomegalovirus-specific immune response in patients with brain cancer.

BACKGROUND: Patients with brain tumor or pancreatic cancer exhibit the poorest prognosis, while immune fitness and cellular immune exhaustion impacts their survival immensely. This work identifies differences in the immune reactivity to the common human pathogens cytomegalovirus (CMV) and Epstein-Barr virus (EBV) between patients with brain tumor in comparison to those with pancreatic cancer and healthy individuals. METHODS: We characterized the humoral and cellular immune responses of patients with brain tumor or pancreatic cancer to cytomegalovirus structural protein pp65 (CMV-pp65) as well as Epstein-Barr nuclear antigen-1 (EBNA-1) by whole-blood assay and ELISA. RESULTS: Anti-CMV-pp65 plasma immunoglobulin gamma (IgG) titers were significantly lower in patients with brain tumor compared to healthy donors and patients with pancreatic cancer. Among the responding patients with GBM, those with a weak anti-CMV IgG response also had a decreased median overall survival (p = 0.017, 667 vs 419 days) while patients with brain tumor showed a generally suppressed anti-CMV immune-reactivity. Patients with brain tumor exhibited a significantly lower interferon gamma (IFNγ) response to EBNA-1 and CMV-pp65 compared to patients with pancreatic cancer or healthy donors. This antigen-specific response was further amplified in patients with brain tumor upon conditioning of whole blood with IL-2/IL-15/IL-21. Exclusively in this setting, among the responding patients with GBM, those exhibiting a EBV-specific cellular immune response above the median also displayed an increased median overall survival pattern compared to weak responders (753 vs 370 days, p < 0.001). CONCLUSIONS: This report provides (i) a fast and easy assay using common viral antigens and cytokine stimulation to screen for immune fitness/exhaustion of patients with brain tumor in comparison to pancreatic cancer and healthy individuals and (ii) EBV/CMV-induced IFNγ production as a potential marker of survival in patients with brain tumor.

Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas.

Lung granulomas develop upon Mycobacterium tuberculosis (Mtb) infection as a hallmark of human tuberculosis (TB). They are structured aggregates consisting mainly of Mtb-infected and -uninfected macrophages and Mtb-specific T cells. The production of NO by granuloma macrophages expressing nitric oxide synthase-2 (NOS2) via l-arginine and oxygen is a key protective mechanism against mycobacteria. Despite this protection, TB granulomas are often hypoxic, and bacterial killing via NOS2 in these conditions is likely suboptimal. Arginase-1 (Arg1) also metabolizes l-arginine but does not require oxygen as a substrate and has been shown to regulate NOS2 via substrate competition. However, in other infectious diseases in which granulomas occur, such as leishmaniasis and schistosomiasis, Arg1 plays additional roles such as T-cell regulation and tissue repair that are independent of NOS2 suppression. To address whether Arg1 could perform similar functions in hypoxic regions of TB granulomas, we used a TB murine granuloma model in which NOS2 is absent. Abrogation of Arg1 expression in macrophages in this setting resulted in exacerbated lung granuloma pathology and bacterial burden. Arg1 expression in hypoxic granuloma regions correlated with decreased T-cell proliferation, suggesting that Arg1 regulation of T-cell immunity is involved in disease control. Our data argue that Arg1 plays a central role in the control of TB when NOS2 is rendered ineffective by hypoxia.

Potential of immunomodulatory agents as adjunct host-directed therapies for multidrug-resistant tuberculosis.

Treatment of multidrug-resistant tuberculosis (MDR-TB) is extremely challenging due to the virulence of the etiologic strains of Mycobacterium tuberculosis (M. tb), the aberrant host immune responses and the diminishing treatment options with TB drugs. New treatment regimens incorporating therapeutics targeting both M. tb and host factors are urgently needed to improve the clinical management outcomes of MDR-TB. Host-directed therapies (HDT) could avert destructive tuberculous lung pathology, facilitate eradication of M. tb, improve survival and prevent long-term functional disability. In this review we (1) discuss the use of HDT for cancer and other infections, drawing parallels and the precedent they set for MDR-TB treatment, (2) highlight preclinical studies of pharmacological agents commonly used in clinical practice which have HDT potential, and (3) outline developments in cellular therapy to promote clinically beneficial immunomodulation to improve treatment outcomes in patients with pulmonary MDR-TB. The use of HDTs as adjuncts to MDR-TB therapy requires urgent evaluation.

Host-directed therapies for antimicrobial resistant respiratory tract infections.

PURPOSE OF REVIEW: Antimicrobial-resistant respiratory tract infections (AMR-RTIs) are increasing, presenting important management challenges worldwide. Current management of AMR-RTI patients focuses on pathogen-directed antimicrobial treatment. Overt lung inflammation, parenchymal damage, and ineffective immune activation perpetrate increased patient morbidity and mortality. Immunomodulatory and tissue-regenerative host-directed therapies (HDT) may improve treatment outcomes. HDTs under investigation for improving AMR-RTI treatment outcomes are reviewed. RECENT FINDINGS: Various HDTs are being developed or evaluated for adjunctive AMR-RTI treatment. α-1 antitrypsin was shown to reduce Pseudomonas aeruginosa burden in the airways of cystic fibrosis patients. Cellular therapy by reinfusing autologous bone marrow-derived MSCs into MDR/XDR-TB patients shows promise, whereas adjunctive T cell-based therapies are considered. Cytotoxic therapy using etoposide, a topoisomerase II-inhibiting anticancer drug extends survival of patients with severe influenza H1N1 infection-induced hemophagocytic lymphohistiocytosis. Two other novel HDT candidates, DAS181 and resveratrol show antiinfluenza effects. Novel kinase inhibitors SB203580 (MAPK-2 antagonist) and LY294002 (phosphoinositide-3 kinases antagonist) exhibit promising anti-MERS-CoV activity. Palivizumab, an anti-RSV monoclonal antibody, effectively prevents RSV infection in high-risk paediatric populations. T-cell therapy is currently considered for adjunctive HDT of azole-resistant pulmonary aspergillosis. SUMMARY: Novel HDTs may revolutionize future treatment regimens for AMR-RTIs. Well designed multisite clinical trials are now necessary to accelerate progress.

B in TB: B Cells as Mediators of Clinically Relevant Immune Responses in Tuberculosis.

The protective role of B cells and humoral immune responses in tuberculosis infection has been regarded as inferior to cellular immunity directed to the intracellular pathogen Mycobacterium tuberculosis. However, B-cell-mediated immune responses in tuberculosis have recently been revisited in the context of B-cell physiology and antigen presentation. We discuss in this review the diverse functions of B cells in tuberculosis, with a focus on their biological and clinical relevance to progression of active disease. We also present the peptide microarray platform as a promising strategy to discover unknown antigenic targets of M. tuberculosis that could contribute to the better understanding of epitope focus of the humoral immune system against M. tuberculosis.

T-Cell Therapy: Options for Infectious Diseases.

The emergence of drug-resistant tuberculosis is challenging tuberculosis control worldwide. In the absence of an effective vaccine to prevent primary infection with Mycobacterium tuberculosis and tuberculosis disease, host-directed therapies may offer therapeutic options, particularly for patients with multidrug-resistant and extensively drug-resistant tuberculosis where prognosis is often limited. CD8(+) and CD4(+) T cells mediate antigen-specific adaptive cellular immune responses. Their use in precision immunotherapy in clinical conditions, especially in treating cancer as well as for prevention of life-threatening viral infections in allogeneic transplant recipients, demonstrated safety and clinical efficacy. We review key achievements in T-cell therapy, including the use of recombinant immune recognition molecules (eg, T-cell receptors and CD19 chimeric antigen receptors), and discuss its potential in the clinical management of patients with drug-resistant and refractory tuberculosis failing conventional therapy.

A novel F(420) -dependent anti-oxidant mechanism protects Mycobacterium tuberculosis against oxidative stress and bactericidal agents.

Mycobacterium tuberculosis (Mtb) is an aerobic bacterium that persists intracellularly in host macrophages and has evolved diverse mechanisms to combat and survive oxidative stress. Here we show a novel F(420) -dependent anti-oxidant mechanism that protects Mtb against oxidative stress. Inactivation of the fbiC gene in Mtb results in a cofactor F(420) -deficient mutant that is hypersensitive to oxidative stress and exhibits a reduction in NADH/NAD(+) ratios upon treatment with menadione. In agreement with the recent hypothesis on oxidative stress being an important component of the pathway resulting in cell death by bactericidal agents, F(420) (-) mutants are hypersensitive to mycobactericidal agents such as isoniazid, moxifloxacin and clofazimine that elevate oxidative stress. The Mtb deazaflavin-dependent nitroreductase (Ddn) and its two homologues Rv1261c and Rv1558 encode for an F(420) H(2) -dependent quinone reductase (Fqr) function leading to dihydroquinones. We hypothesize that Fqr proteins catalyse an F(420) H(2) -specific obligate two-electron reduction of endogenous quinones, thereby competing with the one-electron reduction pathway and preventing the formation of harmful cytotoxic semiquinones, thus protecting mycobacteria against oxidative stress and bactericidal agents. These findings open up an avenue for the inhibition of the F(420) biosynthesis pathway or Fqr-class proteins as a mechanism to potentiate the action of bactericidal agents.

Preclinical efficacy and pharmacokinetics of an RNA-encoded T cell-engaging bispecific antibody targeting human claudin 6.

We present the preclinical pharmacology of BNT142, a lipid nanoparticle (LNP)-formulated RNA (RNA-LNP) encoding a T cell-engaging bispecific antibody that monovalently binds the T cell marker CD3 and bivalently binds claudin 6 (CLDN6), an oncofetal antigen that is absent from normal adult tissue but expressed on various solid tumors. Upon BNT142 RNA-LNP delivery in cell culture, mice, and cynomolgus monkeys, RNA is translated, followed by self-assembly into and secretion of the functional bispecific antibody RiboMab02.1. In vitro, RiboMab02.1 mediated CLDN6 target cell-specific activation and proliferation of T cells, and potent target cell killing. In mice and cynomolgus monkeys, intravenously administered BNT142 RNA-LNP maintained therapeutic serum concentrations of the encoded antibody. Concentrations of RNA-encoded RiboMab02.1 were maintained longer in circulation in mice than concentrations of directly injected, sequence-identical protein. Weekly injections of mice with BNT142 RNA-LNP in the 0.1- to 1-µg dose range were sufficient to eliminate CLDN6-positive subcutaneous human xenograft tumors and increase survival over controls. Tumor regression was associated with an influx of T cells and depletion of CLDN6-positive cells. BNT142 induced only transient and low cytokine production in CLDN6-positive tumor-bearing mice humanized with peripheral blood mononuclear cells (PBMCs). No signs of adverse effects from BNT142 RNA-LNP administration were observed in mice or cynomolgus monkeys. On the basis of these and other findings, a phase 1/2 first-in-human clinical trial has been initiated to assess the safety and preliminary efficacy of BNT142 RNA-LNP in patients with CLDN6-positive advanced solid tumors (NCT05262530).

Preclinical characterization of an mRNA-encoded anti-Claudin 18.2 antibody.

IMAB362/Zolbetuximab, a first-in-class IgG1 antibody directed against the cancer-associated gastric-lineage marker CLDN18.2, has recently been reported to have met its primary endpoint in two phase 3 trials as a first-line treatment in combination with standard of care chemotherapy in CLDN18.2-positive Her2 negative advanced gastric cancer. Here we characterize the preclinical pharmacology of BNT141, a nucleoside-modified RNA therapeutic encoding the sequence of IMAB362/Zolbetuximab, formulated in lipid nanoparticles (LNP) for liver uptake. We show that the mRNA-encoded antibody displays a stable pharmacokinetic profile in preclinical animal models, mediates CLDN18.2-restricted cytotoxicity comparable to IMAB362 recombinant protein and inhibits human tumor xenograft growth in immunocompromised mice. BNT141 administration did not perpetrate mortality, clinical signs of toxicity, or gastric pathology in animal studies. A phase 1/2 clinical trial with BNT141 mRNA-LNP has been initiated in advanced CLDN18.2-expressing solid cancers (NCT04683939).

Targeting Neoepitopes to Treat Solid Malignancies: Immunosurgery.

Successful outcome of immune checkpoint blockade in patients with solid cancers is in part associated with a high tumor mutational burden (TMB) and the recognition of private neoantigens by T-cells. The quality and quantity of target recognition is determined by the repertoire of 'neoepitope'-specific T-cell receptors (TCRs) in tumor-infiltrating lymphocytes (TIL), or peripheral T-cells. Interferon gamma (IFN-γ), produced by T-cells and other immune cells, is essential for controlling proliferation of transformed cells, induction of apoptosis and enhancing human leukocyte antigen (HLA) expression, thereby increasing immunogenicity of cancer cells. TCR αß-dependent therapies should account for tumor heterogeneity and availability of the TCR repertoire capable of reacting to neoepitopes and functional HLA pathways. Immunogenic epitopes in the tumor-stroma may also be targeted to achieve tumor-containment by changing the immune-contexture in the tumor microenvironment (TME). Non protein-coding regions of the tumor-cell genome may also contain many aberrantly expressed, non-mutated tumor-associated antigens (TAAs) capable of eliciting productive anti-tumor immune responses. Whole-exome sequencing (WES) and/or RNA sequencing (RNA-Seq) of cancer tissue, combined with several layers of bioinformatic analysis is commonly used to predict possible neoepitopes present in clinical samples. At the ImmunoSurgery Unit of the Champalimaud Centre for the Unknown (CCU), a pipeline combining several tools is used for predicting private mutations from WES and RNA-Seq data followed by the construction of synthetic peptides tailored for immunological response assessment reflecting the patient's tumor mutations, guided by MHC typing. Subsequent immunoassays allow the detection of differential IFN-γ production patterns associated with (intra-tumoral) spatiotemporal differences in TIL or peripheral T-cells versus TIL. These bioinformatics tools, in addition to histopathological assessment, immunological readouts from functional bioassays and deep T-cell 'adaptome' analyses, are expected to advance discovery and development of next-generation personalized precision medicine strategies to improve clinical outcomes in cancer in the context of i) anti-tumor vaccination strategies, ii) gauging mutation-reactive T-cell responses in biological therapies and iii) expansion of tumor-reactive T-cells for the cellular treatment of patients with cancer.

Immunometabolism: new insights and lessons from antigen-directed cellular immune responses.

Modulation of immune responses by nutrients is an important area of study in cellular biology and clinical sciences in the context of cancer therapies and anti-pathogen-directed immune responses in health and disease. We review metabolic pathways that influence immune cell function and cellular persistence in chronic infections. We also highlight the role of nutrients in altering the tissue microenvironment with lessons from the tumor microenvironment that shapes the quality and quantity of cellular immune responses. Multiple layers of biological networks, including the nature of nutritional supplements, the genetic background, previous exposures, and gut microbiota status have impact on cellular performance and immune competence against molecularly defined targets. We discuss how immune metabolism determines the differentiation pathway of antigen-specific immune cells and how these insights can be explored to devise better strategies to strengthen anti-pathogen-directed immune responses, while curbing unwanted, non-productive inflammation.

Immunometabolism and Pulmonary Infections: Implications for Protective Immune Responses and Host-Directed Therapies.

The biology and clinical efficacy of immune cells from patients with infectious diseases or cancer are associated with metabolic programming. Host immune- and stromal-cell genetic and epigenetic signatures in response to the invading pathogen shape disease pathophysiology and disease outcomes. Directly linked to the immunometabolic axis is the role of the host microbiome, which is also discussed here in the context of productive immune responses to lung infections. We also present host-directed therapies (HDT) as a clinically viable strategy to refocus dysregulated immunometabolism in patients with infectious diseases, which requires validation in early phase clinical trials as adjuncts to conventional antimicrobial therapy. These efforts are expected to be continuously supported by newly generated basic and translational research data to gain a better understanding of disease pathology while devising new molecularly defined platforms and therapeutic options to improve the treatment of patients with pulmonary infections, particularly in relation to multidrug-resistant pathogens.

Latent TB Infection (LTBI) - Mycobacterium tuberculosis pathogenesis and the dynamics of the granuloma battleground.

Latent tuberculosis infection (LTBI) is established in over 90% of persons infected with Mycobacterium tuberculosis (Mtb), from whom new active TB cases will arise. Understanding the spatio-temporal dynamics of host immune responses in LTBI granulomas is essential to designing effective post-exposure therapies that inhibit progression to TB. Information arising from cancer studies and other modalities - where local chronic inflammation leads to immunopathology - can help provide insights into the biological pathways at play in LTBI granulomas. Translational studies using patient material as well as LTBI+ donor-derived tissue samples are instrumental in understanding the various components of granuloma dynamics, immunological landscapes therein and how this could help to identify therapeutic targets. Deep sequencing technologies may aid to decipher the genetic changes in lung granuloma and blood samples from LTBI+ individuals associated with progression to active TB disease. This may lead to advancement of development of targeted Host-Directed Therapies (HDTs) and their evaluation as adjunct TB therapies for improving treatment outcomes for LTBI and pulmonary TB.

Improving treatment outcomes for MDR-TB - Novel host-directed therapies and personalised medicine of the future.

Multidrug-resistant TB (MDR-TB) is a major threat to global health security. In 2017, only 50% of patients with MDR-TB who received WHO-recommended treatment were cured. Most MDR-TB patients who recover continue to suffer from functional disability due to long-term lung damage. Whilst new MDR-TB treatment regimens are becoming available, conventional drug therapies need to be complemented with host-directed therapies (HDTs) to reduce tissue damage and improve functional treatment outcomes. This viewpoint highlights recent data on biomarkers, immune cells, circulating effector molecules and genetics which could be utilised for developing personalised HDTs. Novel technologies currently used for cancer therapy which could facilitate in-depth understanding of host genetics and the microbiome in patients with MDR-TB are discussed. Against this background, personalised cell-based HDTs for adjunct MDR-TB treatment to improve clinical outcomes are proposed as a possibility for complementing standard therapy and other HDT agents. Insights into the molecular biology of the mechanisms of action of cellular HDTs may also aid to devise non-cell-based therapies targeting defined inflammatory pathway(s) in Mtb-driven immunopathology.

Microbes as Master Immunomodulators: Immunopathology, Cancer and Personalized Immunotherapies.

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.