Abstract
Appreciation for genomic and immune heterogeneity in cancer has grown though the relationship of these factors to treatment response has not been thoroughly elucidated. To better understand this, we studied a large cohort of melanoma patients treated with targeted therapy or immune checkpoint blockade (n = 60). Heterogeneity in therapeutic responses via radiologic assessment was observed in the majority of patients. Synchronous melanoma metastases were analyzed via deep genomic and immune profiling, and revealed substantial genomic and immune heterogeneity in all patients studied, with considerable diversity in T cell frequency, and few shared T cell clones (<8% on average) across the cohort. Variables related to treatment response were identified via these approaches and through novel radiomic assessment. These data yield insight into differential therapeutic responses to targeted therapy and immune checkpoint blockade in melanoma, and have key translational implications in the age of precision medicine.
Highlights
Major breakthroughs in melanoma treatment have been made through the use of targeted therapy[1] and immune checkpoint blockade.[2, 3] responses are heterogeneous and are not always durable.[4]
Considering the heterogeneity in therapeutic responses to both targeted therapy and immune checkpoint blockade, and knowledge gained from pre-existing literature,[5] we investigated the role of genomic heterogeneity in synchronous tumors from a subset of these patients who underwent resection of multiple metastases for therapeutic purposes (n = 33 tumors from 15 patients)
Heterogeneity in therapeutic responses was observed in the vast majority of patients studied (83% of patients on targeted therapy and on immune checkpoint blockade) with differences of 10% or more when comparing multiple synchronous metastases within each given patient, with a median difference in tumor growth of 28 and 23% for patients treated with targeted therapy and immune checkpoint blockade, respectively (Fig. 1a, b, Supplementary Table S1A-B, and Supplementary Table S2)
Summary
Major breakthroughs in melanoma treatment have been made through the use of targeted therapy[1] and immune checkpoint blockade.[2, 3] responses are heterogeneous and are not always durable.[4]. Considering the heterogeneity in therapeutic responses to both targeted therapy and immune checkpoint blockade, and knowledge gained from pre-existing literature,[5] we investigated the role of genomic heterogeneity in synchronous tumors from a subset of these patients who underwent resection of multiple metastases for therapeutic purposes (n = 33 tumors from 15 patients). This included patients who were treated with targeted therapy or immune checkpoint blockade, as well as several patients who were naïve to systemic treatment (Supplementary Fig. S1A-S15A and Supplementary Table S3). These studies demonstrated that though a considerable number of neoantigens are shared
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