Genomic and immune heterogeneity are associated with differential responses to therapy in melanoma

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.

Integrated proteogenomic analysis of metastatic thoracic tumors identifies APOBEC mutagenesis and copy number alterations as drivers of proteogenomic tumor evolution and heterogeneity

“…Major advances have been made in the treatment of metastatic tumors, including lung adenocarcinoma and thymic carcinoma, through immunotherapies such as immune checkpoint blockade 63,64 . Nonetheless, only a subset of patients responds and metastases within a given patient may respond differently due to immune heterogeneity 65 . Even without immunotherapy, metastases within a patient may also have differing tumor immune microenvironments, as we demonstrate within thymic carcinoma patient RA006 and as has been recently shown within an ovarian cancer patient 66 .…”

Technical Note: An IBEX adaption toward image biomarker standardization

“…Image biomarker explorer is an open‐source tool for radiomic feature calculation made available by the MD Anderson Cancer Center, and it has already been reliably used for radiomic studies by several institutions around the world . Recently, a paper was published that shares guidelines and experiences using this software .…”

“…Image biomarker explorer is an open-source tool for radiomic feature calculation made available by the MD Anderson Cancer Center, and it has already been reliably used for radiomic studies by several institutions around the world. [27][28][29][30][31][32][33] Recently, a paper was published that shares guidelines and experiences using this software. 34 Image biomarker explorer allows the straightforward calculation of eight feature categories: shape, intensity direct, intensity-histogram, intensityhistogram Gaussian fit, gray-level co-occurrence matrix, gray-level run length matrix, neighborhood gray tone difference matrix, and gradient orient histogram.…”

Spatially resolved analyses link genomic and immune diversity and reveal unfavorable neutrophil activation in melanoma

“…M odern treatment paradigms increasingly expose patients with metastatic melanoma to multiple treatment modalities through the course of their disease 1 . Immune checkpoint blockade in particular has revolutionized the therapeutic landscape, yet durable clinical benefit remains limited to a subset of patients 2,3 . Numerous biomarker studies aiming to elucidate why the majority of patients fail to respond have revealed both immune and genomic contributors to therapeutic activity [3][4][5][6] , but incorporation of such factors into clinical practice is not yet routine.…”

“…Intra-and inter-tumoral heterogeneity can influence lesionspecific and overall patient response to therapy 2,7 , and may contribute significantly to tumor-immune evasion 2,8 . Studying the influence of intratumoral heterogeneity (ITH) using standard approaches such as bulk tumor sequencing or single-cell sequencing generally loses spatial information.…”