Platelets harness the immune response to drive liver cancer

Mala K. Maini1 and Anna Schurich Division of Infection and Immunity, University College London, London WC1 E6JF, United Kingdom

epatocellular carcinoma velopment of procarcinogenic mutations numerous and have a low threshold for (HCC) is a common and highly and ultimately HCC. activation, they have been proposed to H lethal tumor that is currently So where do platelets come into this perform a sentinel function within the the third-leading cause of scenario? Previous groundbreaking work immune system, acting as pivotal medi- cancer-related deaths (1). Hepatitis B from Iannacone et al. (8) revealed an un- ators of cellular communication. As they virus (HBV) is responsible for more than precedented role for activated platelets do not leave the circulation, the main 50% of HCC cases worldwide, making it in mediating CTL-induced liver damage in opportunity for platelets to interact with mouse models of acute viral hepatitis. In the second most important known car- immune cells is thought to arise in the the study of Sitia et al. (2), from the same liver and spleen, where they may become cinogen for all types of cancer. Although laboratory, the authors go on to show that activated in response to damaged endo- prevention of HBV infection by im- platelet activation is a critical driver of the thelium. The mechanism by which pla- plementation of universal infant vacci- fatal sequelae of chronic HBV infection. telets can interact with T cells to nation strategies is starting to have an To do this, Sitia et al. (2) take advantage enhance their local accumulation and impact on the subsequent incidence of of a mouse model that has previously been promote pathologic processes in the HCC (1), there remains a huge burden of- shown to allow persistent, high-level ex- setting of HBV remains to be elucidated. disease in store for the 400 million people pression of the HBsAg transgene in One plausible candidate is CD154 estimated to be already infected with this all hepatocytes, and to result in the de- (CD40 ligand), which is abundantly ex- virus. There is therefore a pressing need to velopment of high rates of HCC in pressed by activated platelets, in develop a better understanding of how a CD8 T cell-dependent manner (9). In amounts shown to be sufficient to aug- HBV infection triggers the development this elegant study, in 540 mice carefully ment lymphocyte function (12) in addi- of HCC, so that earlier intervention can monitored for their lifetime, Sitia et al. tion to triggering an inflammatory prevent this complication of persistent in- (2) demonstrate that the administration of reaction in endothelial cells (13). In- fection. Remarkable findings by Sitia et al. drugs able to block platelet activation terestingly, platelets are also estimated in PNAS (2) shed new light on the patho- [aspirin and clopidogrel (Asp/Clo)] to be the major repository for TGF-β in potently reduces the development of genesis of HBV-related liver cancer, the body (11), raising the possibility that HCC, thereby markedly enhancing sur- antiplatelet therapy could diminish the revealing a surprising effect of antiplatelet vival. The development of cirrhosis cannot fi drugs in preventing its development. release of this pro brogenic cytokine. be assessed in this model, but, importantly, Thus,inadditiontopromotingthe HBV is a hepatotropic DNA virus that fi the authors also observe signi cant ame- clearance of a number of pathogens (11), is not directly cytopathic; the resultant fi lioration in the progression of liver brosis. platelets are emerging as potent drivers liver disease is instead mediated by the Reductions in these outcomes are accom- immune responses it triggers (3). HBV of immune-mediated tissue damage. panied by a decrease in the number of A caveat of the study by Sitia et al. (2) is infects only humans and chimpanzees, fi fi HBV-speci c CD8 and nonspeci c in- the fact that the transgenic mouse model making it challenging to decipher the flammatory cells accumulating in the livers immune correlates of viral control and that had to be used to allow the de- of the transgenic mice expressing high velopment of HCC expressed only HBsAg, disease pathogenesis. Many mechanistic levels of the HBV surface protein (i.e., insights have come from the application of precluding assessment of the impact of the HBsAg) (Fig. 1) (2). Although platelets full virion. A number of viral factors, such mouse models such as the one used by could have procarcinogenic effects in- Sitia et al. (2), in which an HBV transgene as host cell genomic integration and dependent of T cells, Sitia et al. (2) show transactivation of oncogenes by other viral is expressed at high level in the liver, and that antiplatelet drugs are unable to block the resultant tolerance of the immune proteins have been implicated in the de- carcinogenesis in a model of liver cancer velopment of HCC (3, 4). The mouse system is overcome by transfer of HBV- that is not dependent on an inflammatory primed T cells from a nontransgenic syn- fi model used by Sitia et al. (2, 9) suggests in ltrate (2). They therefore conclude that that the immune response to HBV is geneic strain (4). Taken together, studies the capacity of Asp/Clo to block the in- fi in these different hosts have concluded necessary and suf cient to trigger liver trahepatic accumulation and/or expan- cancer. However, viral factors may play an that the HBV-specific CD8 T-cell re- sion of CTL is responsible for the sponse is a key player in triggering viral important secondary role, promoted by striking reductions in HCC. the chronic inflammatory environment. control and liver disease. A strong, func- This work makes an exciting addition to tionally efficient CD8 T-cell response is This model also does not allow any the growing body of literature revealing an assessment of the negative impact that a pivotal component of the coordinated unappreciated role for platelets within the antiplatelet drugs, and the consequent immune response able to control acute immune system. Platelets are tiny (2 μm) reduction in numbers of HBV-specific HBV infection (5). By contrast, an in- anucleate cells, but their simple structure T cells, might have on viremia and in- adequate virus-specific T-cell response in is deceptive; they express mRNA and can fectivity. Similarly, the possibility that Asp/ the setting of persistent infection can trig- synthesize nascent proteins as well as Clo will reduce T cells able to provide ger recurrent hepatocyte damage, amplified storing those they have taken up (10). by the influx of a large non–antigen- Platelets have a large number of in- specificinflammatory infiltrate (6, 7). tracellular granules containing immuno- Hepatocyte death initiates the laying down modulatory ligands, cytokines, and Author contributions: M.K.M. and A.S. wrote the paper. of scar tissue, resulting in progressive chemokines; they can secrete more than The authors declare no conflict of interest. hepatic fibrosis and eventually cirrhosis, 300 different proteins, many of which are See companion article on pages E2165 and 12854. whereas hepatocyte regeneration in an not involved in their primary function of 1To whom correspondence should be addressed. E-mail: m. inflammatory milieu promotes the de- hemostasis (11). Because they are so [email protected].

12840–12841 | PNAS | August 7, 2012 | vol. 109 | no. 32 www.pnas.org/cgi/doi/10.1073/pnas.1210296109 Downloaded by guest on September 28, 2021 COMMENTARY

Untreated model HBV A Non-specific infiltrate T cell

Fig. 1. Inhibiting platelet activation can Fibrin ameliorate the development of HBV-in- duced immune-mediated HCC. (A) Acti- B Hepatocellular Carcinoma Chronic inflammation vated platelets promote the accumulation leads to development fi of fibrosis and HCC of HBsAg-speci c CD8 T cells in the liver. Upon recognition of hepatocytes ex- pressing HBV antigen, specific T cells produce inflammatory cytokines, in- ducing chemokines that recruit additional antigen-nonspecific immune cells. (B) Re- C Aspirin/Clopidogrel treatment petitive cycles of hepatocyte death and regeneration in the milieu of chronic liver inflammation lead to the development of fibrosis and HCC. Transformed hep- Reduced T cell infiltrate Transformed hepatocytes (HCC) atocytes lose the expression of viral anti- inhibits development gens and can no longer be recognized by of fibrosis and HCC CD8 T cells. (C) Suppressing platelet acti- Activated Platelet vation by Asp/Clo treatment significantly Resting Platelet decreases the number of HBV-specific CD8 Hepatocyte Chemokine T cells and secondary nonspecificinfiltrate, Inflammatory cytokine HBsAg ameliorating liver injury and fibrosis and reducing the development of HCC.

tumor surveillance needs to be considered; approach to the prevention of HCC? The tended follow-up, but viral load, and the it is possible that the lack of HBsAg use of drugs that antagonize platelet ag- progression of fibrosis, will be easier expression by HCC cells noted in this gregation seems counterintuitive in pa- outcomes to measure. Initial studies study (2) is the end result of T cell-driven tients with liver disease, who are already could use the woodchuck hepatitis virus cancer immunoediting. considered to be at increased risk of model (closely related to HBV) to assess An important aspect of the study by bleeding. However, recent work suggests theimpactofantiplateletdrugsonvire- Sitia et al. (2) is that treatment was started that liver disease may conversely increase mia, liver inflammation, and HCC. only after inflammation was established, thrombotic tendencies, perhaps justifying HCC arises in the context of chronic making it applicable to the clinical situa- trials of antiplatelet drugs in these patients fl tion, in which many patients with HBV are (14). Blocking platelet activation also necroin ammatory liver disease caused by under surveillance before the onset of carries the risk of interfering with their a number of agents in addition to HBV, significant immunopathologic conditions emerging protective roles against various including HCV and alcohol. The striking requires the commencement of treatment. infections, as exemplified by the ability of effects of antiplatelet drugs demonstrated The decrease in viral load achieved with aspirin to block platelet-mediated killing by Sitia et al. (2) should prompt inves- existing nucleos(t)ide inhibitors reduces all of malaria parasites (15). Weighed against tigation of their effects in these related complications of HBV-induced liver dis- this, antiplatelet drugs are widely used to pathological situations and inspire further ease but certainly cannot eliminate the risk prevent cardiovascular disease, and, in research into the underlying mechanisms of HCC (1); in addition, long-term sup- such studies, have additionally been found of interactions between platelets and pressive therapy with these agents is cur- to reduce the rates of overall cancer T cells. rently too expensive for many of the deaths (16). Prospective studies to specif- countries in which HBV is most prevalent. ically address the effects of Asp/Clo on the ACKNOWLEDGMENTS. Work in the authors’ lab Could antiplatelet drugs constitute a sim- development of HCC in patients with is supported by Medical Research Council, ple, well-tolerated, and cheap additional chronic HBV infection will require ex- United Kingdom.

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