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 - Funding Information:
This research was supported by the generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Moon Shots ProgramTM supporting platform assistance from the Cancer Genomics Laboratory. Additional support was provided to PAF from the Cancer Prevention Research Institute of Texas (R1205 01) and Welch Foundation (G-0040). A.M. was supported by the Cancer Prevention and Research Institute of Texas (CPRIT) Research Training Program (RP170067). M.C.A. is supported by a National Health and Medical Research Council of Australia CJ Martin Early Career Fellowship (#1148680). W.R. was supported by the CPRIT Graduate Scholar Award. A.R. is supported by the Kimberley Clark Foundation Award for Scientific Achievement provided by MD Anderson’s Odyssey Fellowship Program. Additional support was provided by the NCI Cancer Center Support Grant (P30-CA16672) to the MDACC Flow Cytometry and Cell Sorting Core Laboratory and NCI #CA16672 to the RPPA Core Facility. The results published here are in part based upon data generated by the TCGA Research Network: https://www.canver.gov/tcga.
Funding Information:
The authors declare the following competing interests: M.C.A. reports advisory board participation and honoraria from Merck Sharp and Dohme, outside the submitted work. Z.A.C. is currently an employee of Medimmune. D.W. is currently an employee of Vedanta Biosciences. CNS is currently an employee of Parker Institute for Cancer Immunotherapy. A.J.L. reports personal fees from Merck, Bristol-Myers Squibb, Novartis, and Roche/Genentech; personal fees and non-financial support from ArcherDX and Beta-Cat; grants and non-financial support from Medimmune/AstraZeneca and Sanofi; and grants, personal fees, and non-financial support from Janssen, all outside the submitted work. P.H. reports consultant or advisor fees from Dragonfly Therapeutics, GlaxoSmithKline, Immatics, and Sanofi. P.S. reports consultant or advisor fees from Bristol-Myers Squibb, GlaxoSmithKline, AstraZeneca, Amgen, Jounce, Kite Pharma, Neon, Evelo, EMD Serono, and Astellas; stock from Jounce, Kite Pharma, Evelo, Constellation, Neon; and has a patent licensed to Jounce, all outside the submitted work. J.P.A. reports stock ownership from Jounce, Neon, BioAtla, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Codiak, Kite Pharma, and consultant or advisor fees from Jounce, Neon, Amgen, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Codiak, BioAlta LLC, Tvardi Therapeutics, and owns patents licensed to Jounce, Merck & BMS. M.T.T. reports personal fees from Myriad Genetics, Seattle Genetics and Novartis LLC, all outside the submitted work. C.N.S., A.R., and J.A.W. are co-inventors on US patent (PCT/US17/53.717) relating to the microbiome, outside of the current work. J.A.W. reports speaker fees from Imedex, Dava Oncology, Omniprex, Illumina, Gilead, Med-Immune, and Bristol-Myers Squibb; consultant/advisor roles or advisory board membership for Roche-Genentech, Novartis, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Merck/MSD, Biothera Pharma, and Microbiome DX; and receives clinical trial support from GlaxoSmithKline, Roche/Genentech, Bristol-Myers Squibb, and Novartis, all outside the current work. M.A.D. reports being the PI of research supported by grants to his institution from Myriad, AstraZeneca, Roche/Genentech, GlaxoSmithKline, Oncothyreon, and Sanofi-Aventis; consulting for NanoString; and advisory board participation for GlaxoSmithKline, Roche/Genentech, Novartis, Array, Bristol-Myers Squibb, Sanofi-Aventis, and Vaccinex. W.J.H. reports research support from Merck, Schering-Plough, GlaxoSmithKline, Bristol-Myers Squibb, and MedImmune, outside the current work. P.A.F. reports consulting for Gene+, outside of the current work. All other authors declare no competing interests.
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 -