Transcriptional regulation and therapeutic modulation of cytotoxic function in tumour-infiltrating CD4+ T cells

The immune system may hold the key to combating cancer. Recent cancer immunotherapy approaches have been focused on boosting or re-invigorating cytotoxic CD8+ T cell function. However, the proportion of patients that do not respond to therapy remains high and some tumours are not targeted by CD8+ T cells.

There is growing recognition that CD4+ T helper cells can also acquire cytotoxic effector function, and that these cells form a key component of the response to cancer and viral infection. However, our understanding of cytotoxic CD4+ T cell derivation and function lags significantly behind that of their CD8+ counterparts and other CD4+ T cell lineages. Identifying factors that regulate the differentiation and function of cytotoxic CD4+ T cells would provide new opportunities to boost the immune response to cancer and viral infection.

We propose to combine genomics and cancer immunology approaches to identify regulatory proteins that control the differentiation and function of cytotoxic CD4+ T cells in tumours and how these mechanisms may be targeted to harness the activity of these cells.

Building on previous work from our labs, we will use genetically modified tumour models to identify the genes through which transcriptional regulators control differentiation of cytotoxic CD4+ T cell precursors. We will also define the nature of a checkpoint that prevents acquisition of cytotoxic function by precursor cells in untreated tumours. Finally, we will determine whether these regulatory mechanisms can be targeted to promote cytotoxic CD4+ T cell function and tumour immunity.

This work will provide knowledge of the factors that control cytotoxic CD4+ T cell function and identify targets through which the activity of these cells can be harnessed in patients.

Recent cancer immunotherapy approaches have been focused on boosting or re-invigorating cytotoxic CD8+ T cell function. However, the proportion of patients that do not respond to therapy remains high and some tumours lack MHC I expression.

There is growing recognition that CD4+ T helper cells can also acquire cytotoxic effector function, and that these cells form a key component of the response to cancer and viral infection. However, we lack information on the factors required for the differentiation and function of cytotoxic CD4+ T cells (CD4+ TCTX), especially in tumours.

We have found that acquisition of cytotoxic function in tumour-infiltrating CD4+ T cells requires the transcriptional repressor Blimp-1 and is antagonised by Bcl6. We have also discovered that although Blimp-1 is necessary for GzmB transcription, GzmB protein production in TEFF is inhibited unless TREG are depleted from the tumour microenvironment.

We propose to combine genomics and tumour immunology approaches to identify regulatory mechanisms that control the differentiation and function of cytotoxic CD4+ T cells in tumours and how these mechanisms may be targeted to enhance the function of these cells in tumour immunity.

We have three research objectives:

1. Understand how Blimp-1 and Bcl6 regulate the differentiation of CD4+ cytotoxic precursors in tumours by applying CUT&Tag and scATAC-seq techniques to genetically modified tumour models.

2. Characterise and modulate a checkpoint that restrains GzmB protein production in CD4+ cytotoxic precursors using blocking antibodies and gene editing in tumour models.

3. Determine whether the Blimp-1/Bcl6 axis can be targeted to promote acquisition of cytotoxic CD4+ T cell function using tumour models and patient-derived xenografts.

This work will provide knowledge of the factors that control cytotoxic CD4+ T cell function and identify targets through which the activity of these cells can be harnessed in patients.