Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Balachandran, Vinod P.; Łuksza, Marta; Zhao, Julia N.; Makarov, Vladimir; Moral, John A.; Remark, Romain; Herbst, Brian T.; Aşkan, Gökçe; Bhanot, Umesh; Şenbabaoğlu, Yasin; Wells, Daniel K.; Cary, Charles Ian Ormsby; Grbovic-Huezo, Olivera; Attiyeh, Marc A.; Medina, Benjamin D.; Zhang, Jennifer; Loo, Jennifer K.; Saglimbeni, Joseph A.; Abu-Akeel, Mohsen; Zappasodi, Roberta; Riaz, Nadeem; Smoragiewicz, Martin; Kelley, Zakiya; Basturk, Olca; Johns, Amber; Mead, R. Scott; Gill, Anthony J.; Chang, David K.; McKay, Skye; Chantrill, Lorraine A.; Chin, Venessa T.; Chou, Angela; Humphris, Jeremy L.; Pajic, Marina; Steinmann, Angela; Arshi, Mehreen; Drury, Ali; Froio, Danielle; Morgan, Ashleigh; Timpson, Paul; Hermann, David; Vennin, Claire; Warren, Sean; Pinese, Mark; Wu, Jianmin; Pinho, Andreia V.; Tucker, Katherine; Andrews, Lesley; Samra, Jaswinder S.; Arena, Jennifer; Pavlakis, Nick; High, Hilda; Mittal, Anubhav; Biankin, Andrew V.; Bailey, Peter J.; Martin, Sancha; Musgrove, Elizabeth A.; Jones, Marc D.; Nourse, Craig; Jamieson, Nigel B.; Stoita, Alina; Williams, David B.; Spigelman, Allan D.; Waddell, Nicola; Pearson, John V.; Patch, Ann‐Marie; Nones, Kátia; Newell, Felicity; Mukhopadhyay, Pamela; Addala, Venkateswar; Kazakoff, Stephen H.; Holmes, Oliver; Leonard, Conrad; Wood, Scott; Xu, Christina; Grimmond, Sean M.; Hofmann, Oliver; Wilson, Peter J.; Christ, Angelika N.; Bruxner, Tim; Asghari, Ray; Merrett, Neil D.; Pavey, Darren; Das, Amitabha; Goodwin, Annabel; Cosman, Peter H.; Ismail, Kasim; O’Connor, Chelsie; Cooper, Caroline; Grimison, Peter; Kench, James G.; Sandroussi, Charbel; Lam, Vincent; McLeod, Duncan; Nagrial, Adnan; Kirk, Judy; James, Virginia; Texler, Michael; Forest, Cindy; Epari, Krishna; Ballal, Mo; Fletcher, David; Mukhedkar, Sanjay; Zeps, Nikolajs; Beilin, Maria; Feeney, Kynan; Nguyen, Nan Q.; Ruszkiewicz, Andrew; Worthley, Chris; Chen, John; Brooke-Smith, Mark E.; Papangelis, Virginia; Clouston, Andrew D.; Martin, Patrick; Barbour, Andrew P.; O’Rourke, Thomas; Fawcett, J.; Slater, Kellee; Hatzifotis, Michael; Hodgkinson, Peter; Nikfarjam, Mehrdad; Eshleman, James R.; Hruban, Ralph H.; Wolfgang, Christopher L.; Hodgin, Mary; Scarpa, Aldo; Lawlor, Rita T.; Beghelli, Stefania; Corbo, Vincenzo; Scardoni, Maria; Bassi, Claudio; Gönen, Mithat; Levine, Arnold J.; Allen, Peter J.; Fearon, Douglas T.; Mérad, Miriam; Gnjatic, Sacha; Iacobuzio‐Donahue, Christine A.; Wolchok, Jedd D.; DeMatteo, Ronald P.; Chan, Timothy A.; Greenbaum, Benjamin; Merghoub, Taha; Leach, Steven D.

doi:10.1038/nature24462

Cited by 930 publications

(958 citation statements)

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“…However, only a fraction of patients respond to such therapies and there is an urgent need to identify predictors of response . These results, and our previous findings of a reduced PC risk among subjects with atopic conditions, strongly suggest that immune recognition of neoantigens, its quantity and quality could contribute to modulate the immune response to emerging preneoplastic clones …”

Section: Discussionmentioning

confidence: 99%

Pancreatic cancer and autoimmune diseases: An association sustained by computational and epidemiological case–control approaches

Gomez‐Rubio

Piñero

Molina‐Montes

et al. 2018

Intl Journal of Cancer

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Deciphering the underlying genetic basis behind pancreatic cancer (PC) and its associated multimorbidities will enhance our knowledge toward PC control. The study investigated the common genetic background of PC and different morbidities through a computational approach and further evaluated the less explored association between PC and autoimmune diseases (AIDs) through an epidemiological analysis. Gene-disease associations (GDAs) of 26 morbidities of interest and PC were obtained using the DisGeNET public discovery platform. The association between AIDs and PC pointed by the computational analysis was confirmed through multivariable logistic regression models in the PanGen European case-control study population of 1,705 PC cases and 1,084 controls. Fifteen morbidities shared at least one gene with PC in the DisGeNET database. Based on common genes, several AIDs were genetically associated with PC pointing to a potential link between them. An epidemiologic analysis confirmed that having any of the nine AIDs studied was significantly associated with a reduced risk of PC (Odds Ratio (OR) = 0.74, 95% confidence interval (CI) 0.58-0.93) which decreased in subjects having ≥2 AIDs (OR = 0.39, 95%CI 0.21-0.73). In independent analyses, polymyalgia rheumatica, and rheumatoid arthritis were significantly associated with low PC risk (OR = 0.40, 95%CI 0.19-0.89, and OR = 0.73, 95%CI 0.53-1.00, respectively). Several inflammatory-related morbidities shared a common genetic component with PC based on public databases. These molecular links could shed light into the molecular mechanisms underlying PC development and simultaneously generate novel hypotheses. In our study, we report sound findings pointing to an association between AIDs and a reduced risk of PC.

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Section: Discussionmentioning

confidence: 99%

Pancreatic cancer and autoimmune diseases: An association sustained by computational and epidemiological case–control approaches

Gomez‐Rubio

Piñero

Molina‐Montes

et al. 2018

Intl Journal of Cancer

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“…These lines of evidence indicate that the common paradigm of immunologically ‘cold’ pancreatic carcinoma has to be modified. In fact, antitumoural immune reactions are found in the vast majority of patients with PDAC,103 and have been associated with improved prognosis 104…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, a recent study by Balachandran et al found that long-term pancreatic cancer survivors following pancreatic resection were more prone to harbour neoantigens with similarity to known microbial peptides 104. This group established a neoantigen quality fitness model, which could guide the development of new vaccine and treatment approaches for the majority of patients with pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

Neeße

Bauer

Öhlund

et al. 2018

Gut

275

222

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Pancreatic ductal adenocarcinoma (PDA) is notoriously aggressive and hard to treat. The tumour microenvironment (TME) in PDA is highly dynamic and has been found to promote tumour progression, metastasis niche formation and therapeutic resistance. Intensive research of recent years has revealed an incredible heterogeneity and complexity of the different components of the TME, including cancer-associated fibroblasts, immune cells, extracellular matrix components, tumour vessels and nerves. It has been hypothesised that paracrine interactions between neoplastic epithelial cells and TME compartments may result in either tumour-promoting or tumour-restraining consequences. A better preclinical understanding of such complex and dynamic network systems is required to develop more powerful treatment strategies for patients. Scientific activity and the number of compelling findings has virtually exploded during recent years. Here, we provide an update of the most recent findings in this area and discuss their translational and clinical implications for basic scientists and clinicians alike.

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“…Balachandran et al 2017; Brown et al 2014; Gros et al 2016; Hodges et al 2017; Lauss et al 2017; Linnemann et al 2015; Luksza et al 2017; Matsushita et al 2012; McGranahan et al 2016; Ock et al 2017; Pritchard et al 2015a; Rizvi et al 2015; Robbins et al 2013; Snyder et al 2014; Tran et al 2016; Van Allen et al 2015; van Rooij et al 2013; Verdegaal et al 2016). While these various tools have an important role to play in the prediction of immunogenic antigens, the majority of the identified epitopes do not initiate an immune response (e.g.…”

Section: Identification Of Neoantigensmentioning

confidence: 99%

“…Balachandran et al 2017; Snyder et al 2014; van Rooij et al 2013) and other forms of immunotherapy, including dendritic cell vaccines [e.g. unpublished observations and Pritchard et al 2015a, assessing patients from clinical trials (O’Rourke et al 2003, 2007)] and adoptive T-cell transfer (e.g.…”

Section: Immunotherapeutic Potential Of Neoantigensmentioning

confidence: 99%

Identifying neoantigens for use in immunotherapy

Hutchison

Pritchard

2018

Mamm Genome

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This review focuses on the types of cancer antigens that can be recognised by the immune system and form due to alterations in the cancer genome, including cancer testis, overexpressed and neoantigens. Specifically, neoantigens can form when cancer cell-specific mutations occur that result in alterations of the protein from 'self'. This type of antigen can result in an immune response sufficient to clear tumour cells when activated. Furthermore, studies have reported that the likelihood of successful immunotherapeutic targeting of cancer by many different methods was reliant on immune response to neoantigens. The recent resurgence of interest in the immune response to tumour cells, in conjunction with technological advances, has resulted in a large increase in the predicted, identified and functionally confirmed neoantigens. This growth in identified neoantigen sequences has increased the contents of training sets for algorithms, which in turn improves the prediction of which genetic mutations may form neoantigens. Additionally, algorithms predicting how proteins will be processed into peptide epitopes by the proteasome and which peptides bind to the transporter complex are also improving with this research. Now that large screens of all the tumour-specific protein altering mutations are possible, the emerging data from assessment of the immunogenicity of neoantigens suggest that only a minority of variants will form targetable epitopes. The potential for immunotherapeutic targeting of neoantigens will therefore be greater in cancers with a higher frequency of protein altering somatic variants. There is considerable potential in the use of neoantigens to treat patients, either alone or in combination with other immunotherapies and with continued advancements, these potentials will be realised.

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Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Cited by 930 publications

References 26 publications

Pancreatic cancer and autoimmune diseases: An association sustained by computational and epidemiological case–control approaches

Pancreatic cancer and autoimmune diseases: An association sustained by computational and epidemiological case–control approaches

Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

Identifying neoantigens for use in immunotherapy

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