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Regulation of T cell fitness and functions in tumour responses
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Authors
Abstract(s)
The immune system, mainly through the action of T cells (and NK), patrols nascent tumours and controls their progression, in a process called immunosurveillance. However, tumours still develop. The failure of tumour control by the immune system is mediated by several escape mechanisms, and the purpose of immunotherapy is to reverse that escape. Substantial advances had been made in this field with the discovery and therapeutic manipulation of immune checkpoints, which are negative regulators of T cell responses. Their discovery was so important that the two pioneer investigators, Tasuku Honjo and James Allison, received the Nobel Prize of Physiology or Medicine in 2018. Clinical blockade of these pathways has shifted the paradigm in the treatment of several types of cancer; however, the efficacy of this strategy is limited to some types of tumours and to an overall minority of patients. This limited efficacy highlights the need of unravelling new mechanisms responsible for T cell regulation in the tumour microenvironment (TME), which we undertook in this thesis.
First, we studied the negative regulation of IL-17-producing γδ (γδ17) T cells, which we and others had previously shown to play paradoxical tumour-promoting roles. We used two murine cancer models consisting in the injection of a melanoma (B16) or a hepatoma (Hepa 1-6) cell line, in the peritoneal cavity or liver, respectively. These anatomic locations are favourable to the induction of γδ17 T cell responses. However, to our surprise, these cells did not expand upon tumour challenge, in comparison to tumour-free controls. Concomitantly to the absence of a γδ17 T cell response, we observed a striking accumulation of neutrophils, leading us to hypothesize that neutrophils could suppress γδ17 T cell responses. Genetic approaches, depletion strategies and in vitro studies collectively demonstrated that tumour-associated neutrophils inhibited γδ17 T cell proliferation, through the production of reactive oxygen species (ROS). Interestingly, γδ17 T cells expressed low levels of antioxidants, particularly glutathione, which rendered them particularly susceptible to oxidative stress. In sum, we unraveled a new mechanism responsible for the regulation of a critical pro-tumoural T cell subset in the tumour microenvironment.
On the other hand, we also investigated mechanisms of positive regulation of T cells, towards the potentiation of their anti-tumour functions. Given that the essential amino acid, methionine, had previously been shown to be required for T cell proliferation and effector function, we tested the effect of its supplementation in tumour-bearing mice. We used an orthotopic murine triple-negative breast cancer (TNBC) model consisting in the injection of the E0771 cell line in the mammary fat pad. We found that methionine supplementation, while not having a direct effect on tumour progression, potentiated the efficacy of suboptimal anti-PD-1 treatment. The combination of anti-PD-1 with methionine led to an increased infiltration of IFNγ-producing γδ (γδIFNγ) T cells and cytotoxic CD8+ T cells in the tumour bed. Both these subsets were required for the increased efficacy of the combination therapy, with γδ T cells seemingly acting upstream of CD8+ T cells, and the latter becoming more effective tumour killers upon combined therapy. While the molecular mediators underlying the increased T cell infiltration and effector function are still to be determined, our data reveal a new avenue to potentiate the anti-tumour function of γδ and CD8+ T cells, through the combination of anti-PD-1 and methionine.
In conclusion, the work presented in this thesis unravels two new mechanisms of T cell regulation in tumours: one that inhibits pro-tumoural T cells and another that potentiates anti-tumour T cell responses. We hope our findings may contribute to the (re)design of more efficacious cancer immunotherapy strategies.
Description
Keywords
Regulação células T Pro-tumorais Antitumorais Stress oxidativo Metionina Regulation T cells Pro-tumoural Anti-tumoural Oxidative stress Methionine