TY - JOUR
T1 - Spatially resolved analyses link genomic and immune diversity and reveal unfavorable neutrophil activation in melanoma
AU - Mitra, Akash
AU - Andrews, Miles C.
AU - Roh, Whijae
AU - De Macedo, Marianna Petaccia
AU - Hudgens, Courtney W.
AU - Carapeto, Fernando
AU - Singh, Shailbala
AU - Reuben, Alexandre
AU - Wang, Feng
AU - Mao, Xizeng
AU - Song, Xingzhi
AU - Wani, Khalida
AU - Tippen, Samantha
AU - Ng, Kwok Shing
AU - Schalck, Aislyn
AU - Sakellariou-Thompson, Donald A.
AU - Chen, Eveline
AU - Reddy, Sangeetha M.
AU - Spencer, Christine N.
AU - Wiesnoski, Diana
AU - Little, Latasha D.
AU - Gumbs, Curtis
AU - Cooper, Zachary A.
AU - Burton, Elizabeth M.
AU - Hwu, Patrick
AU - Davies, Michael A.
AU - Zhang, Jianhua
AU - Bernatchez, Chantale
AU - Navin, Nicholas
AU - Sharma, Padmanee
AU - Allison, James P.
AU - Wargo, Jennifer A.
AU - Yee, Cassian
AU - Tetzlaff, Michael T.
AU - Hwu, Wen Jen
AU - Lazar, Alexander J.
AU - Futreal, P. Andrew
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-15538-9
DO - 10.1038/s41467-020-15538-9
M3 - Article
C2 - 32296058
AN - SCOPUS:85083477594
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1839
ER -