Spatially resolved analyses link genomic and immune diversity and reveal unfavorable neutrophil activation in melanoma
Akash Mitra, Miles C. Andrews, Whijae Roh, Mariana Petaccia de Macêdo, Courtney W. Hudgens, Fernando C. L. Carapeto, Shailbala Singh, Alexandre Reuben, Feng Wang, Xizeng Mao, Xingzhi Song, Khalida Wani, Samantha Tippen, Patrick Kwok‐Shing Ng, Aislyn Schalck, Donald A. Sakellariou-Thompson, Eveline Chen, Sangeetha M. Reddy, Christine N. Spencer, Diana H. Wiesnoski, Latasha Little, Curtis Gumbs, Zachary A. Cooper, Elizabeth M. Burton, Patrick Hwu, Michael A. Davies, Jianhua Zhang, Chantale Bernatchez, Nicholas E. Navin, Padmanee Sharma, James P. Allison, Jennifer A. Wargo, Cassian Yee, Michael T. Tetzlaff, Wen-Jen Hwu, Alexander J. Lazar, P. Andrew Futreal
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.