Abstract
Complex tumor microenvironmental (TME) features influence the outcome of cancer immunotherapy (IO). Here we perform immunogenomic analyses on 67 intratumor sub-regions of a PD-1 inhibitor-resistant melanoma tumor and 2 additional metastases arising over 8 years, to characterize TME interactions. We identify spatially distinct evolution of copy number alterations influencing local immune composition. Sub-regions with chromosome 7 gain display a relative lack of leukocyte infiltrate but evidence of neutrophil activation, recapitulated in The Cancer Genome Atlas (TCGA) samples, and associated with lack of response to IO across three clinical cohorts. Whether neutrophil activation represents cause or consequence of local tumor necrosis requires further study. Analyses of T-cell clonotypes reveal the presence of recurrent priming events manifesting in a dominant T-cell clonotype over many years. Our findings highlight the links between marked levels of genomic and immune heterogeneity within the physical space of a tumor, with implications for biomarker evaluation and immunotherapy response.
Highlights
Complex tumor microenvironmental (TME) features influence the outcome of cancer immunotherapy (IO)
We identify a remarkable link between copy number gain of chromosome 7 and an unfavorable immune composition driven by neutrophil activation recapitulated within The Cancer Genome Atlas (TCGA) melanoma samples and dominating non-responders to checkpoint blockade immunotherapy across multiple published cohorts
As immune infiltrate correlates with overall survival and has been shown to correlate with responsiveness to anti-PD-1 and anti-CTLA-4 immunotherapy, we investigated the significance of such neutrophil signatures in three publicly available immunotherapy-treated melanoma cohorts (n = 119)[5,19,26,27]
Summary
Complex tumor microenvironmental (TME) features influence the outcome of cancer immunotherapy (IO). Sub-regions with chromosome 7 gain display a relative lack of leukocyte infiltrate but evidence of neutrophil activation, recapitulated in The Cancer Genome Atlas (TCGA) samples, and associated with lack of response to IO across three clinical cohorts. 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. Here we perform spatially detailed immune and genomic analysis of three metastatic lesions, including 67 sub-regions of one tumor sampled throughout its entire mass, from a heavily treated but long-term surviving melanoma patient. We identify a remarkable link between copy number gain of chromosome 7 and an unfavorable immune composition driven by neutrophil activation recapitulated within TCGA melanoma samples and dominating non-responders to checkpoint blockade immunotherapy across multiple published cohorts. We identify a long-term persistent T-cell clonotype having potential relevance to vaccine exploration and cellular immunotherapy
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