PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function.

Expansion of antigen-experienced CD8+ T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer1. Interleukin-2 (IL-2) acts as a key regulator of CD8+ cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability2,3. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE2), a known negative regulator of immune response in the tumour microenvironment4,5, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8+ TILs via the PGE2 receptors EP2 and EP4. Mechanistically, PGE2 inhibits IL-2 sensing in TILs by downregulating the IL-2Rγc chain, resulting in defective assembly of IL-2Rβ-IL2Rγc membrane dimers. This results in impaired IL-2-mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE2 signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE2 in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential

India’s ‘silent contestation’ of the EU’s perspective on local ownership

Local ownership has become a central theme in today’s discourse on peacebuilding, with the EU being very vocal in embracing the norm. On the surface, it thus seems that the EU is supported in its perspective on local ownership by the international community at large. Looking more closely at the discourse surrounding peacebuilding practices, it becomes however apparent, that local ownership remains contested, particularly among emerging countries such as India. The chapter, therefore, sets out to explore why and how India is contesting the EU on local ownership, and how far this impacts the legitimacy of the EU’s norm. Using document analysis on India and the EU’s speeches at the UN, as well as policy documents outlining their peacebuilding strategies, the chapter finds that while India is critical of the content of the norm and the degree of its institutionalization, it chooses more indirect modes of contestation, such as ‘silent contestation’. As a result, the European Union has not been receptive to India’s critique. This is amplified, as the EU has developed its perspective on local ownership among like-minded countries, within the OECD-DAC context and hence relies on internal legitimization of the norm