Immune response

Summary

An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellular bacteria, protozoa, helminths, and fungi which could cause serious problems to the health of the host organism if not cleared from the body. In addition, there are other forms of immune response. For example, harmless exogenous factors (such as pollen and food components) can trigger allergy; latex and metals are also known allergens. A transplanted tissue (for example, blood) or organ can cause graft-versus-host disease. A type of immune reactivity known as Rh disease can be observed in pregnant women. These special forms of immune response are classified as hypersensitivity. Another special form of immune response is antitumor immunity. In general, there are two branches of the immune response, the innate and the adaptive, which work t

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Cancer is the second leading cause of death in the world and melanoma is the deadliest type of skin cancer. Although surgery, radiotherapy and chemotherapy are still standard treatments, the discovery of the role played by the immune system in cancer has allowed the development of new treatments, called immunotherapies. The goal of these treatments is to help the immune system eradicate cancerous cells, for example by increasing the anti-tumor response of the patient. In this particular case, the treatment has to activate cytotoxic CD8+ and CD4+ helper T cells against the cancer cells. This can be done by using subunit vaccines composed of tumor antigens, adjuvants and a delivery system, which will be internalized by dendritic cells (DCs) and induce its activation followed by the migration to the lymph nodes where it will educate T cells against specific antigens. Our laboratory has developed two different delivery systems, nanoparticles (NPs) and polymersomes (PSs) that can enhance the vaccineâs immune response by efficiently entering the lymphatic system, due to their size, and drain to the lymph node. Once they reach that location, they will be internalized by DCs and induce an anti-tumor response. In this thesis, we used these two nanocarriers to create a vaccine composed of different nano-adjuvants capable of activating several toll-like receptors simultaneously and test their efficacy at inducing an anti-tumor response in melanoma. We have developed and characterized the different nano-adjuvants, PS-MPLA, PS-CL075 and NP-CpG-B, and demonstrated, in vitro, synergistic effects on DC activation when PS-MPLA + PS-CL075 and PS-MPLA + NP-CpG-B were combined. In vivo, we showed the enhanced immune response with the different nano-adjuvant combinations, but only PS-MPLA + NP-CpG-B was able to delay tumor growth in melanoma. We then tested this vaccine in combination with radiotherapy, mimicking a clinical situation. We first demonstrated an enhanced immune response when combining a high irradiation dose, 15 Gy, with the nano-adjuvant vaccine draining the tumor-draining lymph node. Moreover, the vaccination of NP-CpG-B + PS-MPLA and radiotherapy increased mice survival by 17 days compared to mice only receiving radiotherapy. â Overall, we have demonstrated that combining different nano-adjuvants, targeting the tumor-draining lymph node, with radiotherapy enhanced significantly the survival in a melanoma model. This approach is particularly promising since ionizing radiation is a standard treatment in cancer and our vaccine can be applied to a multitude of cancer since it does not contain any antigen and its composition can easily be modified.

EPFL2018

Dendritic cells (DCs) are crucial antigen-presenting cells that can drastically change the development of an immune response by polarising T helper cells toward a Th1 or a Th2 phenotype. Heligmosomoides polygyrus, a murine model of human helminth, has been shown to strongly down-regulate its host immune response. At the DC level, its excretory/secretory products (HES) modulate the cytokine response and co-stimulatory marker expression to bacterial stimulation in favour of an antiinflammatory environment. A regulatory T cell-inducing TGF[beta]-like activity was also discovered in HES. In this work, we further characterised the immunomodulatory properties of HES and heat-inactivated HES both in vitro, using LPS-pulsed GM-CSF-grown bone marrowderived DCs, and in in vivo adoptive transfer of HES-, bacterial extract- or co-pulsed DCs. To determine if the TGF[beta], C-type lectin receptors (CLRs) or toll-like receptors (TLRs) were implicated in this immunomodulation, we treated DCs with blocking antibodies, chemical kinase inhibitors and grew DCs from knockout mice. These studies revealed that HES immunomodulation of DCs was independent of the TGF[beta] receptor, the two CLRs, Dectin-1 and 2, as well as any TLR. Spleen tyrosine kinase (Syk), which is crucial for the signalling of many CLRs, and phosphoinositide 3- kinase seemed not to be needed as well. In an attempt to reduce the number of potential immunomodulators in HES, HES size fractions were tested for their ability to reduce LPS-induced inflammatory cytokine production of DCs. The activity was limited to few fractions, fraction 14 being the most potent. Finally, physical interactions between DCs and biotinylated HES were measured by flow cytometry and revealed that CD24, a molecule required for HES interactions with B cells, was implicated, but not crucial. HES binding to CD24-/- DCs was reduced, but the LPS-induced cytokines and co-stimulatory markers levels were still down-regulated upon HES co-treatment.

2011

Cancer is a leading cause of death worldwide. Understanding the underlying mechanisms that lead to tumor escape and evasion is pivotal for the design of new therapeutic applications. This thesis takes an immunobioengineering approach, and navigates through identifying the immunological parameters relevant in the tumor microenvironment, proposing and developing a strategy in response to address these parameters using nanosized drug and antigen carriers. It is widely accepted that changes in the immunological equilibriumof the tumor microenvironment are crucial for the progression, dissemination and metastasis of a developing tumor. Motivated by tumors' natural secretion of CCL21, a chemokine known for dendritic (DC) migration towards the lymphatics, and for attracting DC and T cells in the lymph node (LN), we perturbed the physiological secretion of CCL21 of B16-F10 melanomas, deriving both a knock-down (CCL21low) and an over-expressing (CCL21high) variant. Interestingly, in immunocompetent mice, growth in CCL21-secreting tumors had an advantage over the CCL21low sub-clones and was CCR7 dependent. CCL21low tumors harbored more antigen specific T cells, while CCL21-secreting, more T regulatory cells (Tregs), which also correlated with subsequent biochemical polarization. Moreover, CCL21-secreting tumors formed a reticular fibroblastic (FRC) network (ERTR7+gp38+CCL21+) reminiscent of the lymphoid tissue of the paracortex (T cell zone) within LNs. The lymphoidlike stroma was orchestrated by the recruitment of CCR7+ adult lymphoid tissue inducers (LTis), responsible for LN formation during embryogenesis, present only in the CCL21-secreting tumors. In mice lacking LTis (Rorc(γt)-deficient) control tumors displayed impaired growth, suggesting that tumor growth is stroma dependent. In addition, the stroma of control or CCL21high tumors was infiltrated by more myeloid suppressor cells (MDSCs) than in CCL21low variant. MDSCs are a heterogeneous population of immature myeloid precursor cells that repress T cell activation and antigen presentation in chronic inflammation and cancer, hampering the efficacy of anti-tumoral vaccinations. CCL21's ability to protect allografts was further demonstrated in non-syngeneic recipients and in ectopically CCL21 transduced βTC tumor models. By mimicking secondary lymphoid organs, tumors may hi-jack and modulate the immune response from immunogenic to tolerogenic to allow for growth and metastasis. Intrigued by the excessive stroma infiltration of MDSCs in CCL21-secreting tumors, we performed a detailed spatiotemporal biodistribution analysis of ultrasmall (sub 50 nm) nanoparticles (NPs) in naïve and tumor bearing mice. Intradermally administered NPs rapidly drained to the LNs and spleen and persistently targetedmajor phagocytic populations that play a key role in hosting an immune response in naïve and tumor bearing mice. Furthermore, tumor-induced myeloid compartments, mainlyMDSCs, were highly targeted naturally within the tumormicroenvironment and spleen (tumor macroenvironment) 12 h post administration, without the use of site specific ligand. Following the MDSCs' natural preference towards phagocytosing NPs, and taking advantage of their excessive reductive cytoplasm, we designed a macromolecular pro-drug formulation that bears a cytotoxic payload and can be released in highly reductive microenvironments. Specifically, we engineered a reducible delivery system of 6-tioguanine (TG) in various formulations. Remarkably, bothMDSC compartments were ablated, monocytic ∼20 fold (CD11b+Ly6c+), polymorphonuclear ∼100 fold (CD11b+Ly6g+), for at least 7 d after administration in tumor bearing mice. As the bioidstribution revealed that apart from MDSCs, other antigen presenting cells (APCs) have phagocytosed NPs, we observed only a ∼2 fold decrease in APCs, suggesting that the rest could be used for vaccination. Taking into account that cancer vaccines and cancer immunotherapy rely on the efficient antigen presentation and education of naïve T cells by professional APCs, we explored the ability of NPs to deliver antigens in the appropriate sub-cellular compartment for antigen presentation and activation of T cells. Using the model antigen ovalbumin, we illustrated that exogenous antigen coupled to NPs by reducible bonds were internalized by DCs in vivo and in vitro. The conjugated antigen was preferentially released from the NPs with a reducible formulation, and was successfully presented in the major histocompatibility complex (MHC) I and II, which lead to activation and proliferation of antigen specific CD8+ and CD4+ T cells in vivo, respectively. Taking together, the nanoparticle platformcould be used efficiently for both inducing cytotoxicity and invoking an immune response. From discovery of new suppressive niches to therapeutical applications, we envisioned a two prong strategy that combined I) a modulatory regime to upset the balance of theMDSC populations both within the tumor microenvoronent and systemically with II) a cancer vaccine with the potential to significantly improve anti-tumoral therapeutic applications. This thesis demonstrated that such an approach is both possible and probable.

EPFL2012

EPFL2018