Evangelos Giampazolias Cancer Immunosurveillance - Evangelos Giampazolias

Dr Evangelos Giampazolias

Evangelos Giampazolias received his BSc in Chemistry (2009) and MSc in Clinical Biochemistry (2012) from the University of Athens in Greece. In 2012, he moved to Glasgow, UK, for his PhD at the CRUK Beatson Institute under the supervision of Professor Stephen Tait. During his PhD, he discovered the pro-inflammatory signals that accompany caspase-independent cell death and their impact on cancer immunity. For this, he was awarded the Institute of Cancer Sciences Prize (2017) and the CRUK Pontecorvo Prize (2018). Evangelos subsequently joined the group of Professor Caetano Reis e Sousa at the Francis Crick Institute in London, UK, as a Postdoctoral Fellow. There, he identified that the plasma actin-scavenging system dampens cancer immunity by hijacking innate immune mechanisms of dead cell sensing in the tumour microenvironment. He was granted an innovation patent (2020) to explore the therapeutic potential of these findings as novel immunotherapies for cancers. Further to this, Evangelos studied the influence of host-microbiome interactions in cancer immunity. He identified components of the host physiology that alter gut microbiota, differentially impacting systemic immune responses to cancer. In 2023, Evangelos established the Cancer Immunosurveillance group at the CRUK Manchester Institute, which focuses on the characterisation of the mechanisms that enable the immune system to recognise and respond to cancer through integration of cues that are elicited by dying cells and commensal microbes.


The immune system constitutes a natural host defence mechanism to life-threatening insults. Although, mainly studied in the context of infectious diseases, it is now precedented that the immune system can inhibit cancer formation by detecting and eradicating malignant cells. Cells of the adaptive immunity called T cells, some of which act as immune killers, are often the spearhead of anti-cancer immunity. Although the success is limited to small fraction of cancer patients, T cell-based immunotherapies have dramatically improved clinical outcome in fatal cancers. Instruction of T cell immunity is a key function of dendritic cells (DC). Like other innate immune sensor cells, DC express a wide repertoire of receptors endowing them with the ability to detect microbial presence and tissue damage. How these functions contribute to anti-cancer immunity remains unclear but dying cancer cells and certain commensal bacterial taxa have been linked to induction of T cell mediated anti-cancer immunity and enhanced responses to immunotherapy.

The scientific interest of the Cancer Immunosurveillance research group

In the Cancer Immunosurveillance group, we combine genetically modified mouse models and tumour engineering to disentangle complex tumour-host interactions that underpin cancer immunity. We focus on two fundamental pillars of host physiology, cell death and microbes, that trigger and shape adaptive anti-cancer immune responses under the umbrella of innate immunity. Using our previously and newly established models, we aim to characterise the mechanisms that couple host sensing of (1) dying cancer cells and (2) commensal microbes to T cell mediated cancer immunity. Our ultimate vision is to contribute to the basic understanding of cancer immunity and pave the way for therapeutic approaches to overcome immunotherapy resistance.


Immune checkpoint blockade (ICB) therapy restores T cell immunity to cancer cells and represents the pinnacle of success for treating patients with advanced cancers. Despite the substantial achievement in clinical care, only a small fraction of patients receiving ICB therapy results in durable responses. Resistance to ICB therapy is often attributed to lack of pre-existing T cell mediated anti-cancer responses in the tumour microenvironment (TME). Therefore, the solution to overcome immunotherapy resistance is largely hidden in understanding the origin of T cell mediated cancer immunity. What triggers T cell immunity to cancer? When does T cell mediated cancer immunity fail to be triggered? Can we predict and restore T cell mediated cancer immunity? Previously, we have made significant progress towards these questions.

Cell death sensing in cancer immunity

Immune detection of dying tumour cells can elicit cancer immunity when the host permits it

Cell death is frequently triggered in the TME due to tumour suppressor mechanisms and anti-cancer therapy. DC can sense cell debris and can often elicit antigen-specific CD8+ cytotoxic T lymphocyte (CTL) responses through integration and processing of dead-cell-associated molecular cues. In mice and humans, DNGR-1 (a.k.a CLEC9A), a receptor specifically expressed on type 1 conventional DC (cDC1), binds to F-actin exposed by dying cells and promotes antigen-specific CTL responses. We have previously shown that secreted gelsolin (sGSN), an abundant protein of the plasma that binds to and severs F-actin, inhibits DNGR-1 triggering, dampening anti-cancer immunity, and limiting the efficacy of immunogenic anti-cancer therapies (chemotherapy, radiotherapy, ICB and targeted therapy). In humans, lower intratumoural levels of sGSN transcripts correlate with enhanced signatures of anti-cancer immunity and patient survival. Collectively, our work suggests that evolutionary conserved molecules of the vertebrate physiology (e.g., sGSN) can act as natural barriers to immune detection of dead-cell-associated signals (e.g., F-actin), inhibiting cancer immunity and responses to immunotherapies (Giampazolias E et al, Cell, 2021; Lim KHJ et al, Journal for Immunotherapy of Cancer, 2022).

A. Secreted gelsolin (sGSN) impairs the capacity of type 1 conventional dendritic cells (cDC1), isolated from tumour-draining lymph nodes (tdLN), to prime CD8+ T cells ex vivo. B. Loss of sGSN permits tumour control in a DNGR-1 dependent manner. C. Loss of sGSN enhances the response to immune checkpoint blockade (ICB)-adjuvant therapy. D. Low sGSN transcript levels in human cancer biopsies positively correlate with overall survival; liver cancer (LIHC), head and neck squamous cell carcinoma (HNSC) and stomach adenocarcinoma (STAD). E. Schematic summary: sGSN, component of the plasma actin-scavenging system, secreted by healthy and cancer cells, impairs the ability of the receptor DNGR-1 to recognise dead cells and selectively dampens cross-presentation of tumour antigens by cDC1, acting as a barrier to anti-tumour immunity.

The nature of dead-cell-associated signals impacts cancer immunity

Interestingly, although innate immune cells can detect a variety of molecules associated with cell corpses through engagement of different types of receptors that are expressed on them, the detection of only a limited fraction of these molecular cues are able or sufficient to elicit T cell immunity. Our work suggests that the nature of the dead-cell-associated signals, such as the type of antigen and the class of immunomodulatory molecules, is critical for the robustness of cancer-specific T cell immunity. Specifically, we have found that tumours engineered to express an antigen-associated with the actin-cytoskeleton (LifeAct-OVA) are preferentially controlled by the immune system following detection of cancer cell death by DNGR-1 in comparison to tumours that express a cytoplasmic antigen (OVA) (Giampazolias E et al, Cell, 2021) . Furthermore, we have shown that caspases, the molecular executioners of the programmed cell death termed apoptosis that is frequently triggered in cancer cells, inhibit the de novo synthesis of certain inflammatory mediators (e.g., type I interferons) in dying cells that are necessary for T cell mediated cancer immunity. We have shown that under conditions of partial therapeutic response in mice, engagement of caspase-independent cell death (CICD) is more effective than apoptosis in promoting T cell mediated anti-cancer immune responses that are dependent on the activation of pro-inflammatory signalling pathways and production of inflammatory mediators in dying cells (Giampazolias E et al, Nature Cell Biology, 2017).

A. Schematic summary: sGSN deficiency promotes cancer immune evasion by inhibiting F-actin binding to DNGR-1, thus, leading to impairment of phagosomal rupture in cDC1 and cross-presentation preferentially of neoantigens associated with the actin cytoskeleton. B. Preferential control in sGsn-/- mice of tumours with model antigens engineered to bind F-actin (LA-OVA). C. Schematic summary: Under conditions of partial therapeutic response, tumour caspase-independent cell death (CICD) can have two anti-cancer effects. Engaging mitochondrial outer membrane permeabilisation (MOMP) under caspase inhibited conditions triggers cell death and anti-tumour immunity dependent on inflammatory mediators that are produced as a result of NFκB activation in the dying cells. T cell mediated anti-tumour immunity can kill remaining tumour cells. D. Engagement of CICD but not apoptosis in the tumour microenvironment (TME) triggers tumour regression that is dependent on T cell responses.

We have a long-lasting interest in studying how immune sensors promote cancer immunity by detecting damage in the TME and how mechanisms of the host physiology interfere with this process and therefore differentially modulate cancer immunity. Furthermore, we are interested in characterising mechanisms of acquired resistance to cancer immunity following host detection of cancer cell death that will help in the design of novel anti-cancer therapies.

Microbial sensing in cancer immunity

Host-microbiome interactions shape cancer immunity

Several studies in humans have highlighted a correlation between the prevalence of some intestinal commensal microbes and response to ICB therapy. However, how the abundance and function of gut-resident microbes are regulated and modulate immune responses in the TME remains unclear. Intriguingly, we recently found that the levels of specific host factors (host factors A and B) can determine the ability of gut microbial ecosystems to promote anti-cancer immunity in extraintestinal TME. Manipulation of the stoichiometric ratio of these factors by means of genetics or exogenous supplementation tunes the integration of gut-associated microbial signals to the immune system permitting or suppressing systemic immunity to cancer and response to ICB therapy (Giampazolias E* et al. submitted, *corresponding author) . Therefore, the interaction of dying cancer cells with the immune system is necessary but not sufficient to elicit cancer immunity due to the requirement of immunological permissive environments dictated by the composition and function of the gut microbiome.

Schematic summary: Host-microbiome interactions regulate cancer immunity.

We are currently characterising the cells, molecules and pathways involved in host recognition of gut commensals and study their functional consequence in cancer immunity using mouse models. Furthermore, we aim to characterise the prognostic and therapeutic value of our fundamental discoveries with the vision to find novel strategies for therapeutic intervention.

Selected Publications

Giampazolias E, Pereira da Costa M, Lam KC, Lim KHJ, Cardoso A, Piot C, Chakravarty P, Blasche S, Patel S, Biram A, Castro-Dopico T, Buck MD, Rodrigues RR, Poulsen GJ, Palma-Duran SA, Rogers NC, Koufaki MA, Minutti CM, Wang P, Vdovin A, Frederico B, Childs E, Lee S, Simpson B, Iseppon A, Omenetti S, Kelly G, Goldstone R, Nye E, Suárez-Bonnet A, Priestnall SL, MacRae JI, Zelenay S, Patil KR, Litchfield K, Lee JC, Jess T, Goldszmid RS, Reis E Sousa C. (2024)
Vitamin D regulates microbiome-dependent cancer immunity.
Science 384(6694):428-437. PubMed abstract (PMID: 38662827)

Lim KHJ, Giampazolias E, Schulz O, Rogers NC, Wilkins A, Sahai E, Strid J, Reis e Sousa C. (2022)
Loss of secreted gelsolin enhances response to anticancer therapies.

Journal for Immunotherapy of Cancer 10(9): 1-6. PubMed abstract (PMID: 36162919)

Giampazolias E, Schulz O, Lim KHJ, Rogers NC, Chakravarty P, Srinivasan N, Gordon O, Cardoso A, Buck MD, Poirier EZ, Canton J, Zelenay S, Sammicheli S, Moncaut N, Varsani-Brown S, Rosewell I, Reis e Sousa C. (2021)
Secreted gelsolin inhibits DNGR-1-dependent cross-presentation and cancer immunity.
Cell 184(15):4016-4031.e22. PubMed abstract (PMID: 34081922)

Tunbak H, Enriquez-Gasca R, Tie CHC, Gould PA, Mlcochova P, Gupta RK, Fernandes L, Holt J, van der Veen AG, Giampazolias E, Burns KH, Maillard PV & Rowe HM. (2020)
The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s. 
Nature Communications 11, 5387: 1-15. PubMed abstract (PMID: 33144593)

Minutti CM, Modak RV, Macdonald F, Li F, Smyth DJ, Dorward DA, Blair N, Husovsky C, Muir A, Giampazolias E, Dobie R, Maizels R, Kendall TJ, Griggs DW, Kopf M, Henderson NC, Zaiss DM. (2019)
A macrophage-pericyte axis directs tissue restoration via Amphiregulin-induced TGFβ activation. 
Immunity 50: 645-654. PubMed abstract (PMID: 30770250)

Giampazolias E, Tait SW. (2018)
Caspase-independent cell death: an anti-cancer double-whammy. 
Cell Cycle 17(3):269-270. PubMed abstract (PMID: 29169278)

Giampazolias E, Zunino B, Dhayade S, Bock F, Cloix C, Cao K, Roca A, Lopez J, Ichim G, Proïcs E, Rubio-Patiño C, Fort L, Yatim N, Woodham E, Orozco S, Taraborrelli L, Peltzer N, Lecis D, Machesky L, Walczak H, Albert M, Milling S, Oberst A, Ricci JE, Ryan KM, Blyth K, Tait SW. (2017)
Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency.
Nature Cell Biology 19(9): 1116-1129. PubMed abstract (PMID: 28846096)

Woodham E, Paul N, Tyrrell B, Spence H, Swaminathan K, Scribner M, Giampazolias E, Hedley A, Clark W, Kage, F, Marston DJ, Hahn KM, Tait, SWG, Larue L, Brakebusch, CH, Insall, RH, Machesky, LM. (2017)
Coordination by Cdc42 of Actin, Contractility, and Adhesion for Melanoblast Movement in Mouse Skin. 
Current Biology 27: 624-637. PubMed abstract (PMID: 28238662)

Lopez J, Bessou M, Riley JS, Giampazolias E, Todt F, Rochegüe T, Oberst A, Green DR, Edlich F, Ichim G, Tait SW. (2016)
Mito-priming as a method to engineer Bcl-2 addiction. 
Nature Communications 7, 10538: 1-11. PubMed abstract (PMID: 26833356)

Giampazolias E, Tait SW. (2016)
Mitochondria and the hallmarks of cancer. 
FEBS Journal 283(5): 803-14. PubMed abstract (PMID: 26607558)

Ichim G, Lopez J, Ahmed SU, Muthalagu N, Giampazolias E, Delgado ME, Haller M, Riley JS, Mason SM, Athineos D, Parsons MJ, van de Kooij B, Bouchier-Hayes L, Chalmers AJ, Rooswinkel RW, Oberst A, Blyth K, Rehm M, Murphy DJ, Tait SW. (2015)
Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death. 
Molecular Cell 57(5): 860-72. PubMed abstract (PMID: 25702873)


Postdoctoral Fellows
Alexander Vdovin 
Thomas Elliot

Scientific Officer
Pengbo Wang

Graduate Student
Swara Patel

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