Evolution of Neoantigen Landscape during Immune Checkpoint Blockade in Non–Small Cell Lung Cancer
| Autor: | Jillian Phallen, Malcolm V. Brock, Patrick M. Forde, Stephen B. Baylin, Cynthia A. Zahnow, Theresa Zhang, Peter B. Illei, Violeta Beleva Guthrie, Victor E. Velculescu, Vilmos Adleff, Valsamo Anagnostou, Qing Kay Li, James R. White, Neha Wali, Rohit Bhattacharya, Franco Verde, Kellie N. Smith, Robert B. Scharpf, Carolyn Hruban, Kristen Rodgers, Drew M. Pardoll, Rachel Karchin, Julie R. Brahmer, Christos S. Georgiades, Noushin Niknafs, Edward Gabrielson, Hyunseok Kang, Jarushka Naidoo, William H. Sharfman |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Lung Neoplasms Cell cycle checkpoint medicine.medical_treatment Programmed Cell Death 1 Receptor Drug Resistance Cohort Studies Antineoplastic Agents Immunological 0302 clinical medicine Neoplasms Carcinoma Non-Small-Cell Lung Receptors Monoclonal 2.1 Biological and endogenous factors CTLA-4 Antigen Aetiology Non-Small-Cell Lung Lung Cancer integumentary system biology Lung Cancer Antibodies Monoclonal Middle Aged Immunological Nivolumab Oncology 5.1 Pharmaceuticals Antigen 030220 oncology & carcinogenesis Female Immunotherapy Development of treatments and therapeutic interventions Antibody medicine.drug Adult Oncology and Carcinogenesis Receptors Antigen T-Cell Antineoplastic Agents Ipilimumab Article Antibodies 03 medical and health sciences Immune system Antigens Neoplasm Clinical Research medicine Humans Antigens Prevention Carcinoma Janus Kinase 1 Cell Cycle Checkpoints Janus Kinase 2 T-Cell Immune checkpoint Good Health and Well Being 030104 developmental biology Drug Resistance Neoplasm Mutation Immunology biology.protein Neoplasm Immunization |
| Zdroj: | Cancer discovery, vol 7, iss 3 |
| ISSN: | 2159-8290 2159-8274 |
| Popis: | 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 patients with non–small cell lung cancer after initial response to immune checkpoint blockade with anti–PD-1 or anti–PD-1/anti–CTLA-4 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 was associated with changes in T-cell receptor clonality. These analyses provide insight into the dynamics of mutational landscapes during immune checkpoint blockade and have implications for the development of immune therapies that target tumor neoantigens. Significance: Acquired resistance to immune checkpoint therapy is being recognized more commonly. This work demonstrates for the first time that acquired resistance to immune checkpoint blockade can arise in association with the evolving landscape of mutations, some of which encode tumor neoantigens recognizable by T cells. These observations imply that widening the breadth of neoantigen reactivity may mitigate the development of acquired resistance. Cancer Discov; 7(3); 264–76. ©2017 AACR. See related commentary by Yang, p. 250. This article is highlighted in the In This Issue feature, p. 235 |
| Databáze: | OpenAIRE |
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