Division of Infection and Immunity


IIT Seminar | Dr James Reading

05 May 2022, 12:00 pm–1:00 pm

'Weaponising T cell dysfunction to detect and target lung cancer'

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Dr Anne Pesenacker

Dr James Reading (UCL Cancer Institute) will be speaking at the UCL Institute of Immunity and Transplantation Seminar Series on Thursday 28 April (postponed to Thursday 5 May).

All are welcome to attend. Please contact Hanh Gurr (h.gurr@ucl.ac.uk) if you would like to join the seminar, or meet the speaker.

About the speaker

T cells can detect and eliminate mutant cells that arise during our lifetime, but defects in this defence facilitate cancer development, progression and metastasis. Many of these defects remain a mystery, presenting an acute scientific challenge. Determining how key tumour reactive T cells are dysregulated in nascent and metastatic disease may pave the way for a new wave of precision immunoprevention and immunotherapy strategies.

Dr Reading's research focuses on deciphering the progressive dysregulation of tissue resident and systemic CD4 and CD8 T cell responses to mutation encoded neoantigens from health to death, in several unique clinical cohorts representing a range of cancer types. By longitudinally profiling neoantigen-reactive T cells at the functional, transcriptional, phenotypic and epigenetic level we aim to discern novel biomarkers and actionable T cell-intrinsic targets to inform future preventative and therapeutic immuno-oncology regimens.

The Reading Lab recently discovered a program of neoantigen-driven intra-tumoural T cell dysfunction in primary non-small lung cancer (NSCLC), characterised by a tumour-mutational burden (TMB)-dependent conversion of progenitor (TCF1+) to exhausted (TOX+PD1hi) T cell subsets. They found that neoantigen-driven T cell dysfunction (Neo-Dys) defines adverse clinical outcomes in multiple cancers, consistent with a common pathway of fatal immune failure.

To extend this investigation the Reading Lab explored the neoantigen-reactive T cell-intrinsic mechanisms that confer sensitivity to checkpoint inhibition (CPI; i.e. PD-1 or CTLA-4 blockade) in a pan-cancer meta-analysis of over 1000 immunotherapy-treated patients. Their work revealed that neoantigen-reactive T cells expressing chemotactic (e.g. CXCL13, CCR5), type I IFN (FBXO6) and T cell inhibitory (SLA2, IKZF3) genes may promote positive clinical outcomes, consistent with a role for active T cell recruitment and TCR activation in driving CPI responses.

In addition, the Reading Lab underscored the immunogenicity of several neoantigen subtypes and, with their collaborators, are exploring how expression of these key neoepitopes converges with patterns of tumour evolution and T cell differentiation to govern immune elimination vs failure throughout disease.

Finally, the Reading Lab are exploiting surgical resection and neoantigen vaccination as experimental models to assess the impact of (neo)antigen withdrawal and stimulation on T cell dysfunction and immune escape. By systematically analysing functional and dysfunctional neoantigen-specific T cell responses they ultimately hope to pinpoint and prevent the decay of anti-tumour immunity.

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