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. Ce domaine est au carrefour de divers domaines de la biologie nécessitant une compréhension particulière ainsi qu'une approche intégrée des connaissances : l'étude du micro-environnement tumoral, des différentes sous-populations de leucocytes présents dans une zone tumorale à un stade déterminé, des facteurs de transcription activés chez ces diverses cellules, des sous-types tumoraux pouvant influencer la réponse immune… sont autant de paramètres essentiels à décrire. La mise en évidence de nombreux acteurs moléculaires fondamentaux de régulation de la réponse immune durant

Targeting cancer stem cells by T cell engineering

Nicolas Pierre Desbaillets

The identification of cancer stem cells (CSCs) has fundamentally changed the understanding of tumor biology. CSCs drive tumor initiation and long term tumor growth, can cause relapse and are essential for metastatic colonization. These features place cancer stem cells in the focus for cancer therapy. Recently, great advances have been made in the field of cancer adoptive immunotherapy using engineered T cells. Combining both fields of cancer research to generate immune therapies directly targeting CSCs for increased efficacy and long-term anti-tumor effects would generate great hope for cancer patients. Herein, proof of concept is made that chimeric antigen receptor (CARs) T cells killing breast CSCs are capable of eliminating established metastases. Killing of the CSCs modifies the immune environment resulting in the loss of regulatory T cells and in the induction of an endogenous immune response directed against the tumor that is indispensable for treatment success. Antibody mediated ablation of the CAR T cells induced a rapid re-appearance of CSCs and re-establishment of an immunosuppressive environment in the tumor creating a need for continuous targeting of the CSCs. I demonstrate that endogenous T cell responses are less effective against CSCs than the rest of the tumor. Furthermore, proof is made across multiple tumor models, that activated immune cells and inflammation induce dedifferentiation of bulk tumor cells which regain stem-like phenotypes. This observation further emphasizes the importance of directly targeting the CSCs. Studying the interplay between CSCs and the immune system requires syngeneic, immune competent murine models. This greatly limits the transgenic markers that one can use to visualize, track and target CSCs. Herein, we developed different tolerant mouse models to study breast cancer stem cells in vivo. 4T1 breast adenocarcinoma cells were engineered to express hCEA or GFP-based model surface antigens under the control a stem cell specific promoter. These cells, injected into syngeneic model antigen-tolerant mice established lung metastases which were eliminated by CAR T cell therapy. To further validate this approach using endogenous CSC markers, a genetic cancer model (MMTV-PyMT) has been developed, where stem cell Identification is based on CD90 allelic differentiation. Overall, this work highlights an important interplay between CSCs and the immune system. My results suggest that a feedback loop may be created were immune attack induces CSCs, which are immune privileged and escape killing from endogenous T cells. Subsequently, CSCs induce and control an immunosuppressive environment leading to immune escape. This provides a strong rationale to develop CSC-targeted therapies to be administered in combination with immunotherapies.

EPFL2017

Mechanical Immunoengineering of T Cells for Enhanced Cancer Immunotherapy

Kewen Lei

Cancer is one of the leading causes of death globally. Immunotherapy represents one of the most promising cancer treatments inducing complete and durable responses in a fraction of cancer patients. Despite the unprecedented clinical success achieved by T cell-based cancer immunotherapies, there are tremendous outstanding challenges, including low response rate and severe toxicities, which substantially limit the clinical benefits in a majority of cancer patients. At present, enormous efforts have been spent on modulating biochemical interactions for improving the efficacy and safety of T cell-based cancer immunotherapy. Besides biochemical exchanges, mechanical interactions are universal in every step of T cell immunity and are crucial in regulating T cell functions. Thus, immunoengineering approaches that modulate mechanical interactions in T cell immunity hold great promise to improve current cancer immunotherapy. This thesis aims to develop novel mechanical immunoengineering approaches for improving cancer immunotherapy. Specifically, it includes the following parts:Developing a spiky artificial antigen-presenting cell (aAPC) to enhance ex vivo T cell expansion. Ex vivo expansion of T cells is critical in adoptive T cell therapy (ACT) to ensure an effective therapeutic dosage for cancer treatment. By mimicking the dendritic morphology of dendritic cells, I developed a spiky TiO2 microparticle presenting T cell stimulatory ligands as an aAPC to enhance ex vivo T cell expansion. The spiky aAPC outperformed the smooth counterpart, as well as Dynabead®, a standard aAPC used in clinical manufacturing of ACT therapy, for T cell activation and expansion depending on F-actin polymerization in T cells. Therefore, this finding identifies the morphology of aAPCs as a critical parameter to improve ex vivo T cell manufacturing for ACT therapy.Boosting T cell-mediated cytotoxicity by stiffening cancer cells. I discovered that cancer cell softening derived from cholesterol enrichment in the plasma membrane led to resistance to T cell-mediated cytotoxicity. Stiffening cancer cells via membrane cholesterol depletion substantially enhanced T cell-mediated cytotoxicity against cancer cells through augmenting T cell mechanical force but not any known biochemical pathways of T cell-mediated cytotoxicity. Cancer cell stiffening intervention in vivo enhanced the efficacy of ACT therapy in multiple preclinical solid tumor models. Cancer cell softness thus represents a new immune checkpoint of mechanical basis, and therapeutically targeting this mechanical immune checkpoint has the potential to improve the clinical response of T cell-based cancer immunotherapy.Utilizing T cell force as a trigger to achieve specific release of anti-cancer drugs. Specific delivery of T cell supporting drugs and/or anti-cancer drugs into tumors has the potential to increase the response rate of ACT therapy without causing systemic toxicity. To this end, I developed a T cell force-responsive drug release system based on a mesoporous silica microparticle with DNA force sensors as gatekeepers. T cell force as a highly specific signal upon recognizing cancer cells presenting cognate antigens was shown to trigger specific drug release when T cell receptor signaling was activated. Further, the T cell force-responsive drug release system could deliver anti-cancer drugs in vitro and in vivo in a T cell force-dependent manner and holds promise to enhance cancer immunotherapy.

EPFL2022

Targeting cancer stem cells by T cell engineering

Nicolas Pierre Desbaillets

EPFL2017

Mechanical Immunoengineering of T Cells for Enhanced Cancer Immunotherapy

Kewen Lei

EPFL2022

Soft cancer cells squeeze through T cell's grip

Targeting cancer stem cells by T cell engineering

Mechanical Immunoengineering of T Cells for Enhanced Cancer Immunotherapy

Soft cancer cells squeeze through T cell's grip

Targeting cancer stem cells by T cell engineering

Mechanical Immunoengineering of T Cells for Enhanced Cancer Immunotherapy