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Final Report Summary - HYPOXIC TILS (Influence of hypoxia in the tumor microenvironment on the adaptive immune response and cancer immunotherapy.)

CD8+ T lymphocytes respond directly to the immune microenvironment including tissue oxygenation. The response to hypoxia is regulated by the hypoxia inducible transcription factor (HIF). Hypoxia-inducible transcription factors (HIF) have an important role in physiological adaptation to low oxygen availability. Their functions are essential for adaptive changes at the cellular, tissue, and organismal levels. Two HIF transcription factors comprise the best characterized elements of this response: both are oxygen sensitive and their activity can be regulated post-transcriptionally by the von Hippel Lindau (VHL) tumor suppressor complex. HIF-1a is expressed in most mammalian cell types. It has important functional roles in both innate and adaptive immune cells. The role of HIF-2a in the immune system is less clear.

HIF transcription factors are regulated in a complex fashion, and are controlled by many factors other than oxygenation. In the immune system, certain cytokines produced under inflammation and infection can induce both HIF-1a and HIF-2a. In T lymphocytes, HIF-1a is stabilized upon TCR activation and is important driving a metabolic shift to glycolysis, supporting proliferation and effector function.

To better understand the role of HIF in the T cell response against cancer, we have deleted each individual HIF isoform in CD8+ peripheral T cells, and find an essential role for HIF-1a, but not HIF-2a, in the control of T-cell mediated anti-tumour responses. After activation, T cells migrate from secondary lymphoid organs to tumours. Different subsets of T cells infiltrating the tumours correlate with clinical outcomes and prognosis. As a result of HIF-1a deletion in T cells, the ratio of CD8+ to FoxP3+ cells in TILs was significantly reduced, as a result of impaired CD8+ T cell homing into tumours and an intrinsic defect by HIF-1a CD8+ T cells on migration through the endothelial barrier

HIF-1a, but not HIF-2a, is necessary for the acquisition of an effector phenotype, which is characterized by enhanced glycolytic metabolism, production of effector cytokines, costimulatory and checkpoint receptors and cytolytic molecules. HIF-1a deletion resulted in impaired expression of a set of proteins critically involved in CTL mediated tumour rejection. Among them, the production of effector cytokines IFN-γ and TNFa and cytolytic molecules such as Granzyme B was reduced as a result of HIF-1a genetic ablation. These immunologic molecules are key in the process of immunosurveillance against tumours. Costimulatory and checkpoint receptors, such as CD137, GITR, OX40 and TIM3, PD-1, CTLA-4 and LAG-3 are another set of HIF-1a-dependent proteins which are expressed by CTLs and are involved in the fine-tuning of the immune response. Due to the inhibitory role of checkpoint receptors on T cells, they are targets for immunotherapy. Among them, we identified that PD-1 expression in tumour infiltrating lymphocytes was HIF-1a dependent, an important observation given that PD-1 identifies the patient-specific CD8+ tumour-reactive TIL repertoire.
Hypoxia, a feature of the tumour microenvironment, further increases HIF-1a stabilisation in activated CD8+ T cells leading to an enhanced effector function. Genetic deletion of HIF-1a, but not HIF-2a, in CD8+ T lymphocytes accelerates tumour growth a variety of isograft tumour models. HIF-1a deficiency decreases CD8+ T cell infiltration and effector function, resulting in an imbalance between CD8+ effector T cells and CD4+ FoxP3+ T regulatory cells . HIF-1a-deficient antigen-specific CD8+ T cells lack anti-tumour activity in a model of adoptive T cell therapy of cancer.

Systemic pharmacological inhibition of the hypoxia signalling pathway and HIF-targeted therapeutics are anticancer strategies currently being developed.In this context, our data on the important role of HIF in the anti-tumoural effects of T cells indicates that these approaches could also inhibit the adaptive immune response, suggesting that potential combinations of such agents with immunotherapeutic approaches could be a novel strategy to overcome this problem.

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