Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer

By Valsamo Anagnostou, Kellie N. Smith, P. Forde, N. Niknafs, Rohit Bhattacharya, James Robert White, Theresa Zhang, V. Adleff, J. Phallen, Neha Wali and 19 more. Cancer Discovery, 2016

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Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor neoantigens during the emergence of acquired resistance in non-small cell lung cancer patients after initial response to immune checkpoint blockade with anti-PD1 or anti-PD-1/anti-CTLA4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones. Peptides generated from the eliminated neoantigens elicited clonal T cell expansion in autologous T cell cultures, suggesting that they generated functional immune responses. Neoantigen loss occurred through elimination of tumor subclones or through deletion of chromosomal regions containing truncal alterations and were associated with changes in T cell receptor clonality. These analyses provide insights into the dynamics of mutational landscapes during immune checkpoint blockade and have implications for development of immune therapies that target tumor neoantigens.

Subfields: Immunology, Oncology, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/601fe08a9d116802e3a3dfd702367fd90d8cc6a4

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Citations in the corpus

Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer (2017, background): “In lung cancer, to date, neoantigen loss has been associated with acquired resistance to immune checkpoint blockade (21).”
Organoid modeling of the tumor immune microenvironment (2018, background): “Our rapid functional in vitro organoid assessment of anti-PD-1 activity within a clinically relevant 7-day time frame could complement descriptive biomarkers such as PD-L1 IHC, neoantigen burden, or peripheral blood monocyte content (Anagnostou et al., 2017; Carbognin et al., 2015; Garon et al., 201”
Mechanisms of resistance to immune checkpoint inhibitors (2018, background): “Although clonal neoantigens are associated with response to ICI therapy (McGranahan et al, 2016), evolution of the mutational landscape has been described in patients who developed acquired resistance to ICI (Anagnostou et al, 2016).”
Neoantigens: promising targets for cancer therapy (2023, background): “Furthermore, neoantigen loss through the deletion of chromosomal regions or the elimination of tumor subclones can lead to acquired resistance to immunotherapies such as ICBs.(489) Therefore, to compensate for the loss of targetable neoantigens during immunotherapy, personalized neoantigenspecific i”
Acquired Resistance to Immune Checkpoint Inhibitors (2020, background): “Yet, studies of resistance to ICIs that similarly focused on bulk DNA and RNA sequencing of tumor samples have uncovered a limited number of acquired genomic alterations (discussed in more detail below, largely falling in antigen presentation and interferon-γ signaling pathways) (Anagnostou et al., ”
Evaluation of machine learning methods to predict peptide binding to MHC Class I proteins (2017, background): “In particular, peptides that harbor somatic mutations specific to a patient’s tumor, known as neoantigens, can inform treatment [5] [6].”