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Putting a number on neoepitope quality

The acquired by a tumor can Inferred pre-therapy intratumor Predicted dynamics of cell population clonal structure under therapy generate neoepitopes that mediate immune 1 recognition and rejection of the tumor. But X1 F1 F2 F3 there are conflicting reports as to whether for clones: 0 a tumor’s potential neoepitope load is use-

ful as a reliable indicator of immunogenic- X2 ity across cancer types. Two recent papers Clone 1 in Nature shed light on this issue, showing Clone 2 Clone 3 X3 that neoepitope quality and not quantity is n( ) what matters. The work makes strides not Relative cancer cell population size only because of its potential implications for 0

patient selection and therapy development Neoantigens but also because the insights uncovered tell in tumor clone α an important story on the immunological basis of tumor regression. Fitness components T- cell r ecognition Many factors have been implicated in a under immunotherapy MHC pr esentation probability responder signature for patients receiving checkpoint blockade, an antibody-based

approach to unleash tumor-specific T cells. Predicted immunodominant neoantige n But none has been sufficient to reliably select patients who will respond, and the search has continued for predictors of tumor immuno- T F genicity. One puzzling factor has been the α presence of potential neoepitopes— Figure reproduced with permission from ref. 1. derived from tumor-specific mutations that are presented on tumor cells by the be seen as ‘non-self’ and targeted by T cells to known infectious disease-related , major histocompatibility complex (MHC) are increased. as in the work of Łuksza et al.1, aiming to and recognized by T cells. High tumor Robert Vonderheide, director of the estimate the probability that a neoepitope burden is not always associated Abramson Cancer Center at the University will be recognized as ‘non-self’ by the TCR with , and tumors with low of Pennsylvania, says of the approach, “This repertoire. They also find that neoepitope mutational load do sometimes respond to model will be a first-generation attempt; quality, but not quantity, can stratify long- checkpoint blockade or other forms of immu- there’s bound to be refinements, but it’s a very term survivors. notherapy. clever way of assessing the likelihood that These results “reaffirm with modern The work of Łuksza et al.1 and Balachandran a human has a match in the human immunological understanding that even in et al.2 focuses on the ‘quality’ of neoepitopes TCR repertoire.” pancreatic cancer, the plays instead of their numbers and demonstrates Applying their algorithm to cancer types with a role,” says Vonderheide. The idea of esti- that computed neoepitope characteristics are a relatively high mutational burden (melanoma mating differences between the mutant and important determinants of tumor immuno- and non-small cell lung carcinoma), Łuksza wild-type in the thermodynamics of genicity in several cancer types, including et al.1 find that the model can stratify patients MHC binding and TCR recognition is not low mutational burden and aggressive tumor who respond or don’t respond to checkpoint new. But demonstrating that a model incor- types, such as pancreatic cancer. blockade therapy. This finding suggests that porating these factors can help predict patient Łuksza et al.1 develop an algorithm that what makes a tumor different from its host in survival underscores the importance of this considers two major aspects of neoepitope terms of immune recognition can be quanti- biology to immune recognition. It could also recognition: the difference in inferred bind- fied, and that these scores have predictive value help design therapeutic cancer that ing affinity to MHC of the mutant peptide in terms of patient survival. incorporate neoepitopes. 2 © 2018 Nature America, Inc., part of Springer Nature. All rights reserved. All rights part Nature. of Springer Inc., America, Nature © 2018 versus its wild-type version, and the likeli- Balachandran et al. examine a cohort of “Now we understand that there can be hood that the mutant peptide will be recog- pancreatic cancer patients with long-term immune recognition. We have to be smarter nized by T-cell receptors (TCRs) in a patient’s (median 6 years) and short-term (median 0.8 and innovative in finding strategies that tar- repertoire. For the latter estimation, the years) survival. Long-term survivors, who are get this immunology,” says Vonderheide. model considers how well the mutant peptide rare, had greater density of cytotoxic CD8+ “And it will undoubtedly go further than aligns to thousands of T-cell epitopes known T cells, a majority of which were tumor-specific. checkpoint blockade.” to be recognized by human TCRs. The idea Together, but not separately, CD8+ T-cell infil- Irene Jarchum, is that if neoepitopes share characteristics trate and predicted neoepitope quantity were Senior Editor of epitopes known to be recognized by the associated with patient survival. The research- 1. Łuksza, M. et al. Nature 551, 517–520 (2017) immune system, the chances that they will ers then looked at the homology of neoepitopes 2. Balachandran, V.P. et al. Nature 551, 512–516 (2017).

nature biotechnology volume 36 number 2 February 2018 151