Neoantigen quality predicts immunoediting in survivors of pancreatic cancer

Abstract

Cancer immunoediting1 is a hallmark of cancer2 that predicts that lymphocytes kill more immunogenic cancer cells to cause less immunogenic clones to dominate a population. Although proven in mice1,3, whether immunoediting occurs naturally in human cancers remains unclear. Here, to address this, we investigate how 70 human pancreatic cancers evolved over 10 years. We find that, despite having more time to accumulate mutations, rare long-term survivors of pancreatic cancer who have stronger T cell activity in primary tumours develop genetically less heterogeneous recurrent tumours with fewer immunogenic mutations (neoantigens). To quantify whether immunoediting underlies these observations, we infer that a neoantigen is immunogenic (high-quality) by two features—‘non-selfness’ based on neoantigen similarity to known antigens4,5, and ‘selfness’ based on the antigenic distance required for a neoantigen to differentially bind to the MHC or activate a T cell compared with its wild-type peptide. Using these features, we estimate cancer clone fitness as the aggregate cost of T cells recognizing high-quality neoantigens offset by gains from oncogenic mutations. With this model, we predict the clonal evolution of tumours to reveal that long-term survivors of pancreatic cancer develop recurrent tumours with fewer high-quality neoantigens. Thus, we submit evidence that that the human immune system naturally edits neoantigens. Furthermore, we present a model to predict how immune pressure induces cancer cell populations to evolve over time. More broadly, our results argue that the immune system fundamentally surveils host genetic changes to suppress cancer.

Immune evasion impacts the selective landscape of driver genes during tumorigenesis

“…The copyright holder for this preprint this version posted June 22, 2022. ; https://doi.org/10.1101/2022.06.20.496910 doi: bioRxiv preprint patients. A result in line with a recent analysis of pancreatic cancer patients, where Łuksza et al demonstrated that long-term survivors were subjected to strong immune editing, developed genetically less heterogeneous recurrent tumors with fewer neoantigens [16]. These observations highlight the need for a better understanding of the interaction between immune evasion, selection and clinical outcomes.…”

A multispecies framework for modeling adaptive immunity and immunotherapy in cancer

“…While several noteworthy computational models of neoantigen evolution have been published these models consider either a fixed cancer cell population size or calculate death rates as a function of the cumulative immunogenicity of neoantigens expressed by a lineage or clone [2], [15], [44], [45]. No work, to our knowledge, has modeled a growing tumor with dynamic immunopeptidomes and CTL populations.…”

“…Mechanisms for subclonal neoantigen include not only de novo generation, but also through (epi)genomic silencing of extant neoantigens and/or their associated MHC alleles [10], [11]. In humans, studies across multiple cancer types have found that among hundreds of putative neoantigens identified by bioinformatics pipelines, very few (generally < 4) are bona fide immunogenic when tested in ex vivo assays; moreover, those that are immunogenic tend also to be clonal [4], [5], [12]- [15].…”

“…Neoantigen quantity is therefore critical to consider alongside immunogenicity for immune recognition and ICB treatment efficacy [15], [22]. However, the quantitative relationship between immunopeptidome diversity, CTL diversity, and response to ICB is open to further characterization.…”

Antibody-Based Approaches to Target Pancreatic Tumours

“…This resistance can be explained by the complex immunosuppressive landscape of the PDAC microenvironment. It notably impedes tumour infiltration by effector T cells, making immune quiescent tumours (also called immunologically “cold” tumour) [ 92 ], while PDAC cells harbour neoantigens of high quality [ 93 ] that are immunoedited with time in long-term survivors [ 94 ]. Hence, the focus was next to fight this immunosuppressive TME by using various combination therapies, including dual CPIs therapy, CPIs with chemotherapies, radiotherapies or vaccines [ 95 ].…”