Evolution of Neoantigen Landscape during Immune Checkpoint Blockade in Non–Small Cell Lung Cancer

Abstract

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.

A primer on recent developments in cancer immunotherapy, with a focus on neoantigen vaccines

“…Such loss has been seen in checkpoint blockade therapy, where both chromosomal deletion of clonal neoantigens and negative selection of tumor subclones were observed [148] .…”

Immune Checkpoint Inhibitors in the Treatment of Melanoma: From Basic Science to Clinical Application

“…Failure of tumor antigen presentation is a major mechanism by which tumors escape from T-cell-mediated immune recognition (78,79). Analysis of pretreatment and posttreatment tumor samples from patients with nonsmall cell lung cancer treated with checkpoint blockade revealed the loss of several neoantigens from treatment-refractory tumor cell clones (80). These neoantigens were capable of stimulating T-cell responses in vitro, and their loss coincided with the emergence of disease resistance.…”

Emerging uses of biomarkers in lung cancer management: molecular mechanisms of resistance

“…Few mechanisms for acquired resistance have been clearly identified as of yet but better understanding of determinants of efficacy and resistance will be pivotal to allow optimal utilization of these novel agents. Candidate resistance mechanisms might include upregulation of alternate immune checkpoints (101), somatic mutations in HLA or JAK1/JAK2 genes (102,103) and genomic changes resulting in loss of mutation-associated neoantigens in resistant clones (104). Koyama et al (101) analyzed the tumor immune microenvironment in two fully immunocompetent mouse models of lung adenocarcinoma.…”

“…Anagnostou et al (104) performed whole exome sequencing in four patients with NSCLC who developed acquired resistance to PD-1 blockade and compared the results in pre-treatment and post-treatment specimens and identified genomic changes resulting in loss of 7 to 18 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.…”