Publication

Engineering Innate and Adaptive Immunity for Enhanced Cancer Immunotherapy

Min Gao
2023
Thèse EPFL
Résumé

Cancer immunotherapy has become an attractive strategy among different therapeutic modalities over the past few years and has showed great success in the clinic. However, there are many outstanding challenges hindering the current immunotherapies. In my PhD thesis, I aimed to developing bioengineering approaches for engineering innate and adaptive immunity for enhanced cancer immunotherapy. These projects include three major aspects as follows:Activating cGAS-STING pathway using a manganese-incorporated nanocluster. Targeting the stimulator of interferon genes (STING) pathway with cyclic dinucleotides (CDNs), the natural STING agonists, is a promising immunotherapeutic strategy to boost anticancer immunity. The therapeutic benefits of targeting STING pathway have been demonstrated in many preclinical tumor models. However, the clinical application of natural CDNs as therapeutics is greatly hindered by their intrinsic properties, including negative charges, small molecular weight, and high susceptibility to enzymatic degradation. To overcome these limitations, I developed a manganese-based nanocluster (MnP-PEG) as a new STING agonist. Free manganese ions were released once MnP-PEG nanoclusters were endocytosed, and these ions directly activated the cyclic GMP-AMP synthase (cGAS) and augmented cyclic GMP-AMP (cGAMP)-STING binding affinity. MnP-PEG nanocluster, as a monotherapy or in combination with a checkpoint blockade antibody, resulted in significant tumor regression in the subcutaneous B16F10 murine melanoma model without overt toxicities.Enhancing T cell function by scavenging potassium ions within the tumor microenvironment. The tumor microenvironment is known to strongly suppress T cells for their anticancer activities. Among various immune-suppressive mechanisms, the elevation of extracellular potassium (K+) ions released by tumor cell necrosis causes profound suppression of T cell effector function, limiting the tumor regression efficiency of cancer immunotherapy. To address this issue, I utilized sodium zirconium cyclosilicate (ZS-9) as a K+ ion scavenger to relieve the suppression of T cell effector function mediated by excessive K+ ions. When ZS-9 was embedded into a PLGA-PEG-PLGA copolymer-based hydrogel, this system showed good tumor inhibition ability and the promise as a new strategy for cancer immunotherapy.Inhibiting tumor growth with combination of IL-10/Fc and 4-1BB agonist. One of the major limiting factors for T cell-based immunotherapy is T cell exhaustion, which is characterized by low cytokine production, cytotoxicity, and compromised proliferative capacity. Interleukin-10/Fc fusion protein (IL-10/Fc) has been shown to selectively reinvigorate terminally exhausted CD8+ tumor infiltrating lymphocytes, the direct killers of tumor cells. However, the use of IL-10/Fc alone did not achieve optimal antitumor efficiency, and combining it with adoptive T cell transfer or checkpoint inhibitors was necessary. Intratumoral injection also hindered its further application. To this end, I aimed to develop an IL-10/Fc and 4-1BB agonist based bispecific antibody. While the bispecific antibody could significantly target terminally exhausted CD8+ T cells and promote their proliferation, its antitumor efficacy was limited. However, a combination treatment with IL-10/Fc and 4-1BB agonist showed a synergic effect in eradicating established solid tumors, which was a surprising outcome.

À propos de ce résultat
Cette page est générée automatiquement et peut contenir des informations qui ne sont pas correctes, complètes, à jour ou pertinentes par rapport à votre recherche. Il en va de même pour toutes les autres pages de ce site. Veillez à vérifier les informations auprès des sources officielles de l'EPFL.
Concepts associés (35)
Immunologie des tumeurs
L’immunologie des tumeurs (appelée aussi immunologie anti-tumorale ou immuno-oncologie) et son but, l'immunothérapie des cancers, sont une branche de la biologie et de la médecine qui consiste à étudier les relations entre une tumeur et le système immunitaire de l'hôte, afin de concevoir des traitements anticancéreux capables d'exploiter la puissance potentielle d'une réaction immunitaire dirigée contre la tumeur.
Immunothérapie
vignette|Thérapie adoptive par lymphocytes T (non annotée). Les lymphocytes T spécifiques du cancer peuvent être obtenus par fragmentation et isolement des lymphocytes infiltrant la tumeur, ou par génie génétique des cellules du sang périphérique. Les cellules sont activées L' consiste à administrer des substances stimulant les défenses immunitaires du malade pour lutter contre des pathologies installées, le plus souvent des cancers, voire contre des maladies dégénératives.
Transfert adoptif de cellules
Le transfert adoptif de cellules consiste à transférer des cellules dans un hôte, afin de faire bénéficier ce dernier de leurs fonctions immunitaires. Le transfert adoptif est actuellement une stratégie d'immunothérapie extrêmement prometteuse notamment dans les programmes de lutte contre le cancer. En effet, l'efficacité du transfert adoptif de lymphocytes T a été montré dans certains cancers dont le mélanome métastatique, avec une régression tumorale observée chez 50 % des patients.
Afficher plus
Publications associées (171)

Exploration and modulation of mechanical cues for enhanced cancer immunotherapy

Armand Kurum

The advent of immunotherapy, such as immune checkpoint blockade (ICB) and adoptive transfer of cytotoxic lymphocytes, has transformed the clinical care of cancer. However, a significant proportion of patients are resistant to immunotherapy or experience re ...
EPFL2024

A Cluster of Evolutionarily Recent KRAB Zinc Finger Proteins Protects Cancer Cells from Replicative Stress–Induced Inflammation

Didier Trono, Priscilla Turelli, Evaristo Jose Planet Letschert, Filipe Amândio Brandão Sanches Vong Martins, Florian Huber, Olga Marie Louise Rosspopoff, Romain Forey, Sandra Eloise Kjeldsen, Cyril David Son-Tuyên Pulver, Joana Carlevaro Fita

Heterochromatin loss and genetic instability enhance cancer progression by favoring clonal diversity, yet uncontrolled replicative stress leads to mitotic catastrophe and inflammatory responses that promote immune rejection. KRAB domain-containing zinc fin ...
2024

Development of cysteine cathepsin inhibitors combined with cell type-specific delivery for the treatment of B-cell lymphoma and solid tumors

Aaron Simone Petruzzella

Cysteine cathepsins proteases are enzymes that play essential physiological roles, but their activity is also associated to different aspects of cancer progression and to the development of other diseases. Therefore, cysteine cathepsins are relevant and pr ...
EPFL2024
Afficher plus
MOOCs associés (18)
Introduction à l'immunologie (part 1)
Ce cours décrit les mécanismes fondamentaux du système immunitaire pour mieux comprendre les bases immunologiques dela vaccination, de la transplantation, de l’immunothérapie, de l'allergie et des mal
Afficher plus

Graph Chatbot

Chattez avec Graph Search

Posez n’importe quelle question sur les cours, conférences, exercices, recherches, actualités, etc. de l’EPFL ou essayez les exemples de questions ci-dessous.

AVERTISSEMENT : Le chatbot Graph n'est pas programmé pour fournir des réponses explicites ou catégoriques à vos questions. Il transforme plutôt vos questions en demandes API qui sont distribuées aux différents services informatiques officiellement administrés par l'EPFL. Son but est uniquement de collecter et de recommander des références pertinentes à des contenus que vous pouvez explorer pour vous aider à répondre à vos questions.