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