Tumour Immunogenomics and Immunosurveillance

Research Overview

Immunotherapeutics have led to breakthrough improvements in cancer survival, with immune checkpoint inhibitor (CPI) treatments now approved for over a dozen different tumour types. However, typically only 20-40% of patients benefit from immunotherapy, and novel immune targets are urgently needed to expand the proportion of patients who respond to treatment. An effective anti-tumour immune response is underpinned by multiple factors, including the presence of immunogenic HLA-presented peptides, a functional immune cell infiltration into the tumour core, as well ongoing T-cell priming in tertiary or secondary structures. These processes are regulated by a network of costimulatory molecules, as well as influenced by tumour cell intrinsic events, and hence we adopt a systems level understanding of immunotherapy response throughout our work.

Experimentally, there are a lack of model systems able to recapitulate the complexity of immunotherapy response, and instead our lab conducts discovery work utilising patient samples from clinical trials. Multi-omic profiling of clinical samples has already enhanced our understanding of immunotherapy activity, establishing for example tumour mutation burden as a key driver of CPI response and hence validating the neoantigen hypothesis. A key capability of our lab is conducting large-scale integrated analysis of multi-omic datasets, generated directly from patient tumour tissue, in order to identify of the next generation of cancer immunotherapy targets. Working over the last five years we have compiled one of the world’s largest exome/RNAseq datasets from immunotherapy treated patients. This work is now formalised through an international consortium, with in total genomic/transcriptomic data already available from n=1500 patients, across eight tumour types.

Once novel therapeutic targets are identified in patient datasets, we then use a combination of in vitro, ex vivo and in vivo techniques to explore the functional basis of anti-tumour immune response and develop candidate therapeutic approaches. Biologically, a key interest of the lab is the identification of novel sources of tumour specific antigen capable of eliciting an anti-tumour immune response, as well as characterising cellular pathways which can be perturbed to increase tumour cell immunogenicity.

Recent projects

1. Using DNA sequencing data to quantify T cell fraction and therapy response. Bentham R, Litchfield K, Watkins TBK, Lim EL, Rosenthal R, et al.
2. Selection of metastasis competent subclones in the tumour interior. Zhao Y, Fu X, Lopez JI ... Litchfield K. (Coverage in Evening Standard)
3. Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. Litchfield K, Reading JL, Puttick C, Thakkar K, et al. Cell. 2021 Feb 4;184(3): 596-614.e14.
4. Escape from nonsense-mediated decay associates with anti-tumor immunogenicity. Litchfield K, Reading JL, Lim EL, Xu H, et al. Nat Commun. 2020 Jul 30;11(1):3800.

Previous projects

1. Representative Sequencing: Unbiased Sampling of Solid Tumor Tissue. Litchfield K, Stanislaw S, Spain L, Gallegos LL, et al. Cell Rep. 2020 May 5;31(5): 107550.
2. Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal. Turajlic S*, Xu H*, Litchfield K*, et al. 2018 Apr 19;173(3): 595-610.e11.
3. Escape from nonsense-mediated decay associates with anti-tumor immunogenicity. Litchfield K, Reading JL, Lim EL, et al. Nat Commun. 2020 Jul 30;11(1): 3800.
4. Tumour mutational burden: primary versus metastatic tissue creates systematic bias. Schnidrig D, Turajlic S, Litchfield K. Immunooncol Technol. 2019 Dec 16;4:8-14.
5. UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma. Wolf Y, Bartok O, Patkar S, Eli GB, Cohen S, Litchfield K, et al. Cell. 2019 Sep 19;179(1): 219-235.e21.
6. Optimizing panel-based tumor mutational burden (TMB) measurement. Budczies J, Allgäuer M, Litchfield K, Rempel E, et al. Ann Oncol. 2019 Sep 1;30(9): 1496-1506.
7. Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal. Turajlic S*, Xu H*, Litchfield K*, et al. Cell. 2018 Apr 19;173(3): 581-594.e12.
8. Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies. Arce Vargas F, Furness AJS, Litchfield K, et al. Cancer Cell. 2018 Apr 9;33(4): 649-663.e4.
9. The GENIE Is Out of the Bottle: Landmark Cancer Genomics Dataset Released. Litchfield K, Turajlic S, Swanton C. Cancer Discov. 2017 Aug;7(8): 796-798.
10. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Turajlic S*, Litchfield K*, Xu H, et al. Lancet Oncol. 2017 Aug;18(8): 1009-1021.
11. Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor. Litchfield K, Levy M, Orlando G, Loveday C, et al. Nat Genet. 2017 Jul;49(7): 1133-1140.
12. Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility. Litchfield K, Levy M, Dudakia D, Proszek P, et al. Nat Commun. 2016 Dec 20;7: 13840.
13. Genomic evolution and chemoresistance in germ-cell tumours. Taylor-Weiner A, Zack T, O'Donnell E, Guerriero JL ... Litchfield K, et al. Nature. 2016 Nov 30;540(7631): 114-118.
14. Identification of four new susceptibility loci for testicular germ cell tumour. Litchfield K, Holroyd A, Lloyd A, et al. Nat Commun. 2015 Oct 27;6: 8690.
15. Whole-exome sequencing reveals the mutational spectrum of testicular germ cell tumours. Litchfield K, Summersgill B, Yost S, Sultana R, et al. Nat Commun. 2015 Jan 22;6: 5973.

Lab members

• Dr Kevin Litchfield, Group Leader
• Dr Roberto Vendramin, Postdoctoral Research Fellow
• Dr Benjamin Simpson, Postdoctoral Research Fellow
• Dr Alexander Coulton, Postdoctoral Research Fellow
• Dr Hongui Cha, Postdoctoral Research Fellow
• Dr Danwen Qian, Postdoctoral Research Fellow
• Dr. Andrea Casro, Postdoctoral Research Fellow
• Dr. Christopher Pinder, Postdoctoral Research Fellow
• Dr Jun Murai, Visiting Scientist
• Dr Yue Zhao, Visiting Scientist
• Dr Christopher Sng, Visiting Academic Clinical Fellow
• Lorena Liagammari, Senior Research Technician
• Dr. Stephanie Verfuerth, Senior Research Technician
• Krupa Thakkar, PhD Student
• Hongchang Fu, PhD Student 
• Shanila Fernandez Patel, PhD Student
• Evelyn Fitzsimons, PhD Student
• Marcellus Augustine, MBPhD Student
• Kelvin Tsang, PhD Student
• Alice Martin, PhD Student

Our Funders