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

2020-04-15

Mitra, Akash

Andrews, Miles C

Roh, Whijae

De Macedo, Marianna Petaccia

Hudgens, Courtney W

Carapeto, Fernando

Singh, Shailbala

Reuben, Alexandre

Wang, Feng

Mao, Xizeng

Song, Xingzhi

Wani, Khalida

Tippen, Samantha

Ng, Kwok-Shing

Schalck, Aislyn

Sakellariou-Thompson, Donald A

Chen, Eveline

Reddy, Sangeetha M

Spencer, Christine N

Wiesnoski, Diana

Little, Latasha D

Gumbs, Curtis

Cooper, Zachary A

Burton, Elizabeth M

Hwu, Patrick

Davies, Michael A

Zhang, Jianhua

Bernatchez, Chantale

Navin, Nicholas

Sharma, Padmanee

Allison, James P

Wargo, Jennifer A

Yee, Cassian

Tetzlaff, Michael T

Hwu, Wen-Jen

Lazar, Alexander J

Futreal, P Andrew

Journal Article

0000-0002-0633-1615

0000-0003-1231-8641

0000-0002-7395-9939

0000-0002-0434-7605

0000-0001-8312-7485

0000-0003-4510-0382

0000-0003-0364-7443

0000-0003-1059-0940

0000-0002-0977-0912

0000-0001-5412-9860

0000-0003-3438-7576

0000-0002-6395-4499

0000-0001-8663-2671

10.1038/s41467-020-15538-9

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.

link

Nature Communications 2020; 11(1): 1839

Nature Communications