I lead a research group at the Cambridge Institute for Therapeutic Immunology and Infectious Disease, where we work to understand how the immune system interacts with cancer—and how we might harness this knowledge to develop new treatments.
Biography
My path to this work began with a DPhil in Biochemistry from the University of Oxford in 2007, where I studied specialized immune cells called Natural Killer T cells under Professor Frances Platt's supervision. During my first postdoctoral position, jointly supervised by Professors Platt and Vincenzo Cerundolo, I made an unexpected discovery that would shape my research direction: patients with Niemann-Pick type C disease had impaired Natural Killer cell function due to disrupted calcium signalling in cellular compartments called lysosomes. This serendipitous finding revealed an unexpected link between cellular metabolism and immune function.
I then moved to the University of Southern California to investigate how the immune system responds to influenza infection and contributes to asthma development, focusing on the molecular signals that control immune cell activation.
In 2012, I returned to the UK to join the Wellcome Sanger Institute, where I led a team conducting high-throughput studies of immune function in genetically modified mice as part of The Infection and Immunity Immunophenotyping (3i) consortium spearheaded by Professor Adrian Hayday. In 2015, I joined Dr David Adams' Experimental Cancer Genetics group, collaborating with Dr Louise van der Weyden to identify genes that influence how the immune system responds to metastatic cancer cells—work that revealed multiple targets for potential therapeutic intervention.
I established my independent research group in 2021, bringing together expertise in immunology, cancer biology, and large-scale genetic approaches to discover new ways to help the immune system fight cancer.
Research
Cancer cells are masters of immune evasion, developing sophisticated strategies to hide from or suppress the body's natural defences. My group works to understand these interactions between the immune system and developing tumours, with the ultimate goal of translating our discoveries into new therapies for patients.
We take a multi-faceted approach, combining advanced cell analysis techniques (including multi-parameter flow cytometry for detailed immune cell profiling), imaging methods, DNA and RNA sequencing, and various models. A key strength of our work is the use of large-scale genetic engineering tools—particularly unbiased CRISPR screens—that allow us to systematically identify genes and pathways that regulate immune responses to cancer.
Our current research focuses primarily on two types of immune cells that are critical for anti-tumour immunity: Natural Killer cells and CD8 cytotoxic T cells. Through funding from Open Targets, we're pursuing several active projects in this area.
A major challenge in the field is that immune cells often become "exhausted" during chronic exposure to cancer, losing their ability to fight effectively. We're developing models that recapitulate this exhaustion process, allowing us to study it in detail and identify ways to prevent or reverse it. We recently published one such model for mouse CD8 T cells (Manrique-Rincón et al., iScience 2025), and we're expanding this approach to explore other key aspects of anti-tumour immunity.
Ultimately, we aim to uncover new therapeutic targets and strategies that can tip the balance in favour of the immune system, helping it to recognize and eliminate cancer cells more effectively.
Publications
Speak AO, Te Vruchte D, Davis LC, Morgan AJ, Smith DA, Yanjanin NM, Simmons L, Hartung R, Runz H, Mengel E, Beck M, Imrie J, Jacklin E, Wraith JE, Hendriksz C, Lachmann R, Cognet C, Sidhu R, Fujiwara H, Ory DS, Galione A, Porter FD, Vivier E, Platt FM. Altered distribution and function of natural killer cells in murine and human Niemann-Pick disease type C1. Blood. 2014;123(1):51-60. https://pmc.ncbi.nlm.nih.gov/articles/PMC3879905/
van der Weyden L, Arends MJ, Campbell AD, Bald T, Wardle-Jones H, Griggs N, Velasco-Herrera MD, Tuting T, Sansom OJ, Karp NA, Clare S, Gleeson D, Ryder E, Galli A, Tuck E, Cambridge EL, Voet T, Macaulay IC, Wong K, Sanger Mouse Genetics P, Spiegel S, Speak AO*, Adams DJ*. Genome-wide in vivo screen identifies novel host regulators of metastatic colonization. Nature. 2017;541(7636):233-6
https://pmc.ncbi.nlm.nih.gov/articles/PMC5603286/
Ballesteros Reviriego C, Clare S, Arends MJ, Cambridge EL, Swiatkowska A, Caetano S, Abu-Helil B, Kane L, Harcourt K, Goulding DA, Gleeson D, Ryder E, Doe B, White JK, van der Weyden L, Dougan G, Adams DJ, Speak AO. FBXO7 sensitivity of phenotypic traits elucidated by a hypomorphic allele. PLoS One. 2019 Mar 6;14(3):e0212481.
https://pmc.ncbi.nlm.nih.gov/articles/PMC6402633/
Martinelli AW, Wu CP, Vornbäumen T, Coates HW, Jordon LH, Wit N, Sia JJ, Speak AO, Nathan JA. Mapping the genetic landscape of iron metabolism uncovers the SETD2 methyltransferase as a modulator of iron flux. Sci Adv. 2025 Sep 19;11(38).
https://pmc.ncbi.nlm.nih.gov/articles/PMC12442849/
Manrique-Rincón AJ, Foster B, Horswell S, Goulding DA, Adams DJ, Speak AO. Simulating CD8 T cell exhaustion: A comprehensive approach. iScience. 2025 Jun 12;28(7):112897.
