Modelling mechanisms of resistance to T cell-based therapy of solid cancers
Creators: name: Boll, Helena Nike
Publisher: name: Universitäts- und Landesbibliothek Bonn
Year: 2024
Subjects: subject: Onkologie
subject: Immunologie
subject: Immuntherapien
subject: Melanoma
subject: Ovarialkarzinom
subject: Oncology
subject: Immunology
subject: FOS: Clinical medicine
subject: Immunotherapies
subject: Ovarian cancer
subject: ddc:570
subject: ddc:610

description: In the past two decades, T cell-based immunotherapies like immune checkpoint inhibition (ICI) and adoptive cell transfer therapy (ACT) have exhibited remarkable effectiveness in the treatment of cancer. However, despite these advancements, treatment responses among patients vary strongly, and only a small percentage of patients experience long-term benefit. Cancer cells often develop mechanisms to evade immune recognition, leading to therapy resistance. Resistance can occur at any treatment stage and has been shown to be caused by tumour-intrinsic and extrinsic factors often mediated by the tumour immune microenvironment. Using syngeneic mouse melanoma and ovarian cancer models alongside human culture systems, this PhD project aimed to identify and characterise novel mechanisms of therapy resistance. <br> T cell-based immunotherapies can induce strong anti-melanoma responses. However, in a subset of mice, melanomas escape ACT therapy, relapse, and develop resistance to salvage immunotherapy targeting PD-L1. To understand the underlying mechanisms, ex vivo melanoma cell lines were established. Analysis of these lines revealed that reduced induction of MHC I expression upon stimulation with IFN-γ led to impaired T cell recognition. Using sequencing and CRISPR/Cas9-based approaches, this study demonstrated that decreased induction of MHC I resulted from a spontaneous loss-of-function mutation in Nlrc5, a key transcriptional regulator of MHC I expression. Importantly, Nlrc5-deficient melanoma cells grew progressively in NK cell competent hosts, while MHC I deficient melanoma cells were efficiently eliminated by NK cells. ACT experiments further showed that Nlrc5-deficient melanoma cells not only evade NK cell- but at the same time T cell-mediated immunity in vivo. Thus, this study uncovered a novel tumour cell intrinsic mechanism of immune escape that impairs innate and adaptive immune responses. <br> Similar to melanoma, ovarian cancer has been shown to elicit adaptive immune responses, and recent findings indicate that the immune system recognises ovarian tumour-specific mutations. Nonetheless, immunotherapeutic strategies in ovarian cancer have only shown limited efficacy and response rates are much lower than those observed in melanoma. To determine the factors and mechanisms leading to immune escape, good preclinical ovarian cancer mouse models that are targetable by T cells are needed. Utilising CRISPR/Cas9-based techniques, a pathophysiological relevant, advanced-stage ovarian cancer mouse model, enabling in vivo investigations of therapeutic T cell-based approaches and resistance mechanisms was established. In an initial proof-of-concept study, in vivo regression of ovarian cancer cells was observed as an effect of ACT immunotherapy. Tumour regression, however, was followed by tumour recurrence and associated with accumulation of ascites. Malignant ascites presents a unique ovarian cancer immune microenvironment. Utilising a clinically more translatable human culture system, a suppressive effect of patient-derived ascites on T cell function was demonstrated. Ascites-induced suppression of CAR T cell-dependent TNF-α production was revealed as one potential mediator of suppression. <br> Together, studies described in this thesis enabled the identification of a novel intrinsic resistance mechanism to T cell-based immunotherapy in melanoma – a loss-of-function mutation in Nlrc5, while an extrinsic resistance mechanism, ascites-induced T cell suppression, was identified in ovarian cancer. Advancing the understanding of both intrinsic and extrinsic resistance mechanisms is pivotal for the development of novel cancer immunotherapies and the refinement of currently available therapeutic strategies.