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Immunotherapy is a major focus in the fight against cancer and has had astonishing success in some cases, even advanced cancers. However, for unclear reasons, immunotherapy is much less efficacious in other patients. Hence, there is an urgent need to find new avenues to improve this powerful type of therapy.

 

Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells recognize pathogen-infected and cancerous cells via surface receptors that bind to surface-exposed antigens. Intracellular signals caused by receptor activation induce multiple processes, including formation of a contact area with the target cell called immunological synapse. Lytic granules containing cell-killing factors (perforins and granzymes) are released at these synapses through exocytosis (degranulation) to eradicate the target cells. Localization of exocytosis to the immunological synapse ensures that the killing factors are focused on the target cell. Target recognition and elimination are exquisitely controlled by multiple mechanisms to respond to pathogens and cancer cells but not to self-tissues. Hence, enhancing the ability of CTLs and/or NK cells to kill target cells without affecting self-tissues provides a potentially very powerful approach to improve cancer immunotherapy.

 

One avenue to pursue this goal is to potentiate the efficiency of lytic granule degranulation, which is governed by proteins homologous those that control neurotransmitter release at neuronal synapses1 (see ‘Overview’ tab). These include Munc18-2, Munc13-4, Rab27a, RhoG and the SNAREs syntaxin-11 and SNAP-23. There is evidence that VAMP2, VAMP4, VAMP7 and/or VAMP8 act as the V-SNARE, and that Synaptotagmin-2 and/or Synaptotagmin-7 act as calcium sensors1. Building on our experience in studying synaptic vesicle exocytosis, we have started to investigate the molecular mechanisms underlying lytic granule degranulation using AlphaFold models of these proteins, SNARE complex assembly assays and liposome fusion experiments, together with lytic granule exocytosis assays in CTLs. This research is performed in collaboration with Yenan Bryceson. His lab will follow up our studies to test whether strategies designed to enhance lytic granule degranulation emerging from our mechanistic studies can improve cancer immunotherapy.

 

[1] Meeths, M., and Bryceson, Y. T. (2021) Acta Paediatr 110, 2903-2911.

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