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Litchfield Lab UCL

The Tumour Immunogenomics and Immunosurveillance (TIGI) Lab

Group Leader: Dr Kevin Litchfield

Research Overview

Our lab focuses on the genomic and transcriptomic drivers of anti-tumour immune response, using cancer bioinformatics and ex-vivo, in-vivo and in-vitro experimental approaches.

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. 

Recently published research projects

We recently published a spatial evolutionary study in Nature Ecology & Evolution:

Selection of metastasis competent subclones in the tumour interior. Zhao Y, Fu X, Lopez JI, Rowan A, Au L, Fendler A, Hazell S, Xu H, Horswell S, Shepherd STC, Spain L, Byrne F, Stamp G, O'Brien T, Nicol D, Augustine M, Chandra A, Rudman S, Toncheva A, Pickering L, Sahai E, Larkin J, Bates PA, Swanton C, Turajlic S; TRACERx Renal Consortium, Litchfield K. (news coverage)

We recently published our CPI1000+ meta-analysis dataset in Cell:

Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. Kevin Litchfield 1, James L Reading 2, Clare Puttick 3, Krupa Thakkar 1, Chris Abbosh 4, Robert Bentham 4, Thomas B K Watkins 3, Rachel Rosenthal 3, Dhruva Biswas 3, Andrew Rowan 3, Emilia Lim 3, Maise Al Bakir 3, Virginia Turati 5, José Afonso Guerra-Assunção 6, Lucia Conde 6, Andrew J S Furness 7, Sunil Kumar Saini 8, Sine R Hadrup 8, Javier Herrero 6, Se-Hoon Lee 9, Peter Van Loo 10, Tariq Enver 5, James Larkin 7, Matthew D Hellmann 11, Samra Turajlic 12, Sergio A Quezada 13, Nicholas McGranahan 14, Charles Swanton 15. Cell. 2021 Feb 4;184(3):596-614.e14. doi: 10.1016/j.cell.2021.01.002. Epub 2021 Jan 27

We have recently published work indentifying the nonsense mediated decay pathway as a key driver of immunotherapy response, and a pathway which can be perturbed to enhance tumour cell immunogenicity:

Escape from nonsense-mediated decay associates with anti-tumor immunogenicity. Litchfield K, Reading JL, Lim EL, Xu H, Liu P, Al-Bakir M, Wong YNS, Rowan A, Funt SA, Merghoub T, Perkins D, Lauss M, Svane IM, Jönsson G, Herrero J, Larkin J, Quezada SA, Hellmann MD, Turajlic S, Swanton C. Nat Commun. 2020 Jul 30;11(1):3800. doi: 10.1038/s41467-020-17526-5. PMID: 32733040

Our Funders

CRUK
      
MRC
     
rosetress
   
MRA

Previously published research projects

YouTube Widget Placeholderhttps://www.youtube.com/watch?v=RxmpNC1w60A

Representative Sequencing: Unbiased Sampling of Solid Tumor Tissue. Litchfield K, Stanislaw S, Spain L, Gallegos LL, Rowan A, Schnidrig D, Rosenbaum H, Harle A, Au L, Hill SM, Tippu Z, Thomas J, Thompson L, Xu H, Horswell S, Barhoumi A, Jones C, Leith KF, Burgess DL, Watkins TBK, Lim E, Birkbak NJ, Lamy P, Nordentoft I, Dyrskjøt L, Pickering L, Hazell S, Jamal-Hanjani M; PEACE Consortium, Larkin J, Swanton C, Alexander NR, Turajlic S. Cell Rep. 2020 May 5;31(5):107550. doi: 10.1016/j.celrep.2020.107550. PMID: 32375028
 
Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal. Turajlic S*, Xu H*, Litchfield K*, Rowan A, Horswell S, Chambers T, O'Brien T, Lopez JI, Watkins TBK, Nicol D, Stares M, Challacombe B, Hazell S, Chandra A, Mitchell TJ, Au L, Eichler-Jonsson C, Jabbar F, Soultati A, Chowdhury S, Rudman S, Lynch J, Fernando A, Stamp G, Nye E, Stewart A, Xing W, Smith JC, Escudero M, Huffman A, Matthews N, Elgar G, Phillimore B, Costa M, Begum S, Ward S, Salm M, Boeing S, Fisher R, Spain L, Navas C, Grönroos E, Hobor S, Sharma S, Aurangzeb I, Lall S, Polson A, Varia M, Horsfield C, Fotiadis N, Pickering L, Schwarz RF, Silva B, Herrero J, Luscombe NM, Jamal-Hanjani M, Rosenthal R, Birkbak NJ, Wilson GA, Pipek O, Ribli D, Krzystanek M, Csabai I, Szallasi Z, Gore M, McGranahan N, Van Loo P, Campbell P, Larkin J, Swanton C; TRACERx Renal Consortium.Cell. 2018 Apr 19;173(3):595-610.e11. doi: 10.1016/j.cell.2018.03.043. Epub 2018 Apr 12.
 
Selected Publications (for full listing see: https://scholar.google.co.uk/citations?user=jMPt91EAAAAJ&hl=en)
 

Escape from nonsense-mediated decay associates with anti-tumor immunogenicity. Litchfield K, Reading JL, Lim EL, Xu H, Liu P, Al-Bakir M, Wong YNS, Rowan A, Funt SA, Merghoub T, Perkins D, Lauss M, Svane IM, Jönsson G, Herrero J, Larkin J, Quezada SA, Hellmann MD, Turajlic S, Swanton C. Nat Commun. 2020 Jul 30;11(1):3800. doi: 10.1038/s41467-020-17526-5. PMID: 32733040

Representative Sequencing: Unbiased Sampling of Solid Tumor Tissue. Litchfield K, Stanislaw S, Spain L, Gallegos LL, Rowan A, Schnidrig D, Rosenbaum H, Harle A, Au L, Hill SM, Tippu Z, Thomas J, Thompson L, Xu H, Horswell S, Barhoumi A, Jones C, Leith KF, Burgess DL, Watkins TBK, Lim E, Birkbak NJ, Lamy P, Nordentoft I, Dyrskjøt L, Pickering L, Hazell S, Jamal-Hanjani M; PEACE Consortium, Larkin J, Swanton C, Alexander NR, Turajlic S. Cell Rep. 2020 May 5;31(5):107550. doi: 10.1016/j.celrep.2020.107550. PMID: 32375028

Tumour mutational burden: primary versus metastatic tissue creates systematic bias Desiree Schnidrig, Samra Turajlic, Kevin Litchfield.

UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma. Wolf Y, Bartok O, Patkar S, Eli GB, Cohen S, Litchfield K, Levy R, Jiménez-Sánchez A, Trabish S, Lee JS, Karathia H, Barnea E, Day CP, Cinnamon E, Stein I, Solomon A, Bitton L, Pérez-Guijarro E, Dubovik T, Shen-Orr SS, Miller ML, Merlino G, Levin Y, Pikarsky E, Eisenbach L, Admon A, Swanton C, Ruppin E, Samuels Y. Cell. 2019 Sep 19;179(1):219-235.e21. doi: 10.1016/j.cell.2019.08.032. Epub 2019 Sep 12.

Optimizing panel-based tumor mutational burden (TMB) measurement. Budczies J, Allgäuer M, Litchfield K, Rempel E, Christopoulos P, Kazdal D, Endris V, Thomas M, Fröhling S, Peters S, Swanton C, Schirmacher P, Stenzinger A.Ann Oncol. 2019 Sep 1;30(9):1496-1506. doi: 10.1093/annonc/mdz205.

Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal. Turajlic S*, Xu H*, Litchfield K*, Rowan A, Chambers T, Lopez JI, Nicol D, O'Brien T, Larkin J, Horswell S, Stares M, Au L, Jamal-Hanjani M, Challacombe B, Chandra A, Hazell S, Eichler-Jonsson C, Soultati A, Chowdhury S, Rudman S, Lynch J, Fernando A, Stamp G, Nye E, Jabbar F, Spain L, Lall S, Guarch R, Falzon M, Proctor I, Pickering L, Gore M, Watkins TBK, Ward S, Stewart A, DiNatale R, Becerra MF, Reznik E, Hsieh JJ, Richmond TA, Mayhew GF, Hill SM, McNally CD, Jones C, Rosenbaum H, Stanislaw S, Burgess DL, Alexander NR, Swanton C; PEACE; TRACERx Renal Consortium. Cell. 2018 Apr 19;173(3):581-594.e12. doi: 10.1016/j.cell.2018.03.057. Epub 2018 Apr 12.

Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal. Turajlic S*, Xu H*, Litchfield K*, Rowan A, Horswell S, Chambers T, O'Brien T, Lopez JI, Watkins TBK, Nicol D, Stares M, Challacombe B, Hazell S, Chandra A, Mitchell TJ, Au L, Eichler-Jonsson C, Jabbar F, Soultati A, Chowdhury S, Rudman S, Lynch J, Fernando A, Stamp G, Nye E, Stewart A, Xing W, Smith JC, Escudero M, Huffman A, Matthews N, Elgar G, Phillimore B, Costa M, Begum S, Ward S, Salm M, Boeing S, Fisher R, Spain L, Navas C, Grönroos E, Hobor S, Sharma S, Aurangzeb I, Lall S, Polson A, Varia M, Horsfield C, Fotiadis N, Pickering L, Schwarz RF, Silva B, Herrero J, Luscombe NM, Jamal-Hanjani M, Rosenthal R, Birkbak NJ, Wilson GA, Pipek O, Ribli D, Krzystanek M, Csabai I, Szallasi Z, Gore M, McGranahan N, Van Loo P, Campbell P, Larkin J, Swanton C; TRACERx Renal Consortium.Cell. 2018 Apr 19;173(3):595-610.e11. doi: 10.1016/j.cell.2018.03.043. Epub 2018 Apr 12.

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies. Arce Vargas F, Furness AJS, Litchfield K, Joshi K, Rosenthal R, Ghorani E, Solomon I, Lesko MH, Ruef N, Roddie C, Henry JY, Spain L, Ben Aissa A, Georgiou A, Wong YNS, Smith M, Strauss D, Hayes A, Nicol D, O'Brien T, Mårtensson L, Ljungars A, Teige I, Frendéus B; TRACERx Melanoma; TRACERx Renal; TRACERx Lung consortia, Pule M, Marafioti T, Gore M, Larkin J, Turajlic S, Swanton C, Peggs KS, Quezada SA.Cancer Cell. 2018 Apr 9;33(4):649-663.e4. doi: 10.1016/j.ccell.2018.02.010. Epub 2018 Mar 22

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. doi: 10.1158/2159-8290.CD-17-0604.

Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Turajlic S*, Litchfield K*, Xu H, Rosenthal R, McGranahan N, Reading JL, Wong YNS, Rowan A, Kanu N, Al Bakir M, Chambers T, Salgado R, Savas P, Loi S, Birkbak NJ, Sansregret L, Gore M, Larkin J, Quezada SA, Swanton C. Lancet Oncol. 2017 Aug;18(8):1009-1021. doi: 10.1016/S1470-2045(17)30516-8. Epub 2017 Jul 7

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, Law PJ, Migliorini G, Holroyd A, Broderick P, Karlsson R, Haugen TB, Kristiansen W, Nsengimana J, Fenwick K, Assiotis I, Kote-Jarai Z, Dunning AM, Muir K, Peto J, Eeles R, Easton DF, Dudakia D, Orr N, Pashayan N; UK Testicular Cancer Collaboration; PRACTICAL Consortium, Bishop DT, Reid A, Huddart RA, Shipley J, Grotmol T, Wiklund F, Houlston RS, Turnbull C. Nat Genet. 2017 Jul;49(7):1133-1140. doi: 10.1038/ng.3896. Epub 2017 Jun 12

Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility. Litchfield K, Levy M, Dudakia D, Proszek P, Shipley C, Basten S, Rapley E, Bishop DT, Reid A, Huddart R, Broderick P, Castro DG, O'Connor S, Giles RH, Houlston RS, Turnbull C. Nat Commun. 2016 Dec 20;7:13840. doi: 10.1038/ncomms13840

Genomic evolution and chemoresistance in germ-cell tumours. Taylor-Weiner A, Zack T, O'Donnell E, Guerriero JL, Bernard B, Reddy A, Han GC, AlDubayan S, Amin-Mansour A, Schumacher SE, Litchfield K, Turnbull C, Gabriel S, Beroukhim R, Getz G, Carter SL, Hirsch MS, Letai A, Sweeney C, Van Allen EM. Nature. 2016 Nov 30;540(7631):114-118. doi: 10.1038/nature20596

Identification of four new susceptibility loci for testicular germ cell tumour.  Litchfield K, Holroyd A, Lloyd A, Broderick P, Nsengimana J, Eeles R, Easton DF, Dudakia D, Bishop DT, Reid A, Huddart RA, Grotmol T, Wiklund F, Shipley J, Houlston RS, Turnbull C. Nat Commun. 2015 Oct 27;6:8690. doi: 10.1038/ncomms9690

Whole-exome sequencing reveals the mutational spectrum of testicular germ cell tumours. Litchfield K, Summersgill B, Yost S, Sultana R, Labreche K, Dudakia D, Renwick A, Seal S, Al-Saadi R, Broderick P, Turner NC, Houlston RS, Huddart R, Shipley J, Turnbull C. Nat Commun. 2015 Jan 22;6:5973. doi: 10.1038/ncomms6973