Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma

Lymphocytes are key for immune surveillance of tumors, but our understanding of the spatial organization and physical interactions that facilitate lymphocyte anti-cancer functions is limited. We used multiplexed imaging, quantitative spatial analysis, and machine learning to create high-definition m...

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Vydané v:	Cancer cell Ročník 41; číslo 5; s. 871
Hlavní autori:	Gaglia, Giorgio, Burger, Megan L, Ritch, Cecily C, Rammos, Danae, Dai, Yang, Crossland, Grace E, Tavana, Sara Z, Warchol, Simon, Jaeger, Alex M, Naranjo, Santiago, Coy, Shannon, Nirmal, Ajit J, Krueger, Robert, Lin, Jia-Ren, Pfister, Hanspeter, Sorger, Peter K, Jacks, Tyler, Santagata, Sandro
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 08.05.2023
Predmet:	Adenocarcinoma of Lung - genetics Animals CD8-Positive T-Lymphocytes Humans Immunity Immunotherapy - methods Lung Neoplasms - pathology Mice computational biology spatial biology systems biology CyCIF multimodal data integration cancer vaccines spatial profiling immunotherapy lung adenocarcinoma multiplexed imaging
ISSN:	1878-3686, 1878-3686
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Abstract	Lymphocytes are key for immune surveillance of tumors, but our understanding of the spatial organization and physical interactions that facilitate lymphocyte anti-cancer functions is limited. We used multiplexed imaging, quantitative spatial analysis, and machine learning to create high-definition maps of lung tumors from a Kras/Trp53-mutant mouse model and human resections. Networks of interacting lymphocytes ("lymphonets") emerged as a distinctive feature of the anti-cancer immune response. Lymphonets nucleated from small T cell clusters and incorporated B cells with increasing size. CXCR3-mediated trafficking modulated lymphonet size and number, but T cell antigen expression directed intratumoral localization. Lymphonets preferentially harbored TCF1 PD-1 progenitor CD8 T cells involved in responses to immune checkpoint blockade (ICB) therapy. Upon treatment of mice with ICB or an antigen-targeted vaccine, lymphonets retained progenitor and gained cytotoxic CD8 T cell populations, likely via progenitor differentiation. These data show that lymphonets create a spatial environment supportive of CD8 T cell anti-tumor responses.
AbstractList	Lymphocytes are key for immune surveillance of tumors, but our understanding of the spatial organization and physical interactions that facilitate lymphocyte anti-cancer functions is limited. We used multiplexed imaging, quantitative spatial analysis, and machine learning to create high-definition maps of lung tumors from a Kras/Trp53-mutant mouse model and human resections. Networks of interacting lymphocytes ("lymphonets") emerged as a distinctive feature of the anti-cancer immune response. Lymphonets nucleated from small T cell clusters and incorporated B cells with increasing size. CXCR3-mediated trafficking modulated lymphonet size and number, but T cell antigen expression directed intratumoral localization. Lymphonets preferentially harbored TCF1 PD-1 progenitor CD8 T cells involved in responses to immune checkpoint blockade (ICB) therapy. Upon treatment of mice with ICB or an antigen-targeted vaccine, lymphonets retained progenitor and gained cytotoxic CD8 T cell populations, likely via progenitor differentiation. These data show that lymphonets create a spatial environment supportive of CD8 T cell anti-tumor responses. Lymphocytes are key for immune surveillance of tumors, but our understanding of the spatial organization and physical interactions that facilitate lymphocyte anti-cancer functions is limited. We used multiplexed imaging, quantitative spatial analysis, and machine learning to create high-definition maps of lung tumors from a Kras/Trp53-mutant mouse model and human resections. Networks of interacting lymphocytes ("lymphonets") emerged as a distinctive feature of the anti-cancer immune response. Lymphonets nucleated from small T cell clusters and incorporated B cells with increasing size. CXCR3-mediated trafficking modulated lymphonet size and number, but T cell antigen expression directed intratumoral localization. Lymphonets preferentially harbored TCF1+ PD-1+ progenitor CD8+ T cells involved in responses to immune checkpoint blockade (ICB) therapy. Upon treatment of mice with ICB or an antigen-targeted vaccine, lymphonets retained progenitor and gained cytotoxic CD8+ T cell populations, likely via progenitor differentiation. These data show that lymphonets create a spatial environment supportive of CD8+ T cell anti-tumor responses.Lymphocytes are key for immune surveillance of tumors, but our understanding of the spatial organization and physical interactions that facilitate lymphocyte anti-cancer functions is limited. We used multiplexed imaging, quantitative spatial analysis, and machine learning to create high-definition maps of lung tumors from a Kras/Trp53-mutant mouse model and human resections. Networks of interacting lymphocytes ("lymphonets") emerged as a distinctive feature of the anti-cancer immune response. Lymphonets nucleated from small T cell clusters and incorporated B cells with increasing size. CXCR3-mediated trafficking modulated lymphonet size and number, but T cell antigen expression directed intratumoral localization. Lymphonets preferentially harbored TCF1+ PD-1+ progenitor CD8+ T cells involved in responses to immune checkpoint blockade (ICB) therapy. Upon treatment of mice with ICB or an antigen-targeted vaccine, lymphonets retained progenitor and gained cytotoxic CD8+ T cell populations, likely via progenitor differentiation. These data show that lymphonets create a spatial environment supportive of CD8+ T cell anti-tumor responses.
Author	Lin, Jia-Ren Jacks, Tyler Coy, Shannon Naranjo, Santiago Santagata, Sandro Tavana, Sara Z Dai, Yang Pfister, Hanspeter Gaglia, Giorgio Jaeger, Alex M Sorger, Peter K Burger, Megan L Rammos, Danae Ritch, Cecily C Warchol, Simon Crossland, Grace E Krueger, Robert Nirmal, Ajit J
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Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR 97212, USA; School of Medicine, Division of Hematology and Oncology, Oregon Health & Science University, Portland, OR 97212, USA – sequence: 3 givenname: Cecily C surname: Ritch fullname: Ritch, Cecily C organization: Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA – sequence: 4 givenname: Danae surname: Rammos fullname: Rammos, Danae organization: Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA – sequence: 5 givenname: Yang surname: Dai fullname: Dai, Yang organization: Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA – sequence: 6 givenname: Grace E surname: Crossland fullname: Crossland, Grace E organization: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA – sequence: 7 givenname: Sara Z surname: Tavana fullname: Tavana, Sara Z organization: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA – sequence: 8 givenname: Simon surname: Warchol fullname: Warchol, Simon organization: Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; School of Engineering and Applied Sciences, Harvard University, Boston, MA 02134, USA – sequence: 9 givenname: Alex M surname: Jaeger fullname: Jaeger, Alex M organization: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA – sequence: 10 givenname: Santiago surname: Naranjo fullname: Naranjo, Santiago organization: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA – sequence: 11 givenname: Shannon surname: Coy fullname: Coy, Shannon organization: Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA – sequence: 12 givenname: Ajit J surname: Nirmal fullname: Nirmal, Ajit J organization: Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA – sequence: 13 givenname: Robert surname: Krueger fullname: Krueger, Robert organization: Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; School of Engineering and Applied Sciences, Harvard University, Boston, MA 02134, USA – sequence: 14 givenname: Jia-Ren surname: Lin fullname: Lin, Jia-Ren organization: Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA – sequence: 15 givenname: Hanspeter surname: Pfister fullname: Pfister, Hanspeter organization: School of Engineering and Applied Sciences, Harvard University, Boston, MA 02134, USA – sequence: 16 givenname: Peter K surname: Sorger fullname: Sorger, Peter K organization: Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA – sequence: 17 givenname: Tyler surname: Jacks fullname: Jacks, Tyler organization: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA – sequence: 18 givenname: Sandro surname: Santagata fullname: Santagata, Sandro email: ssantagata@bics.bwh.harvard.edu organization: Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: ssantagata@bics.bwh.harvard.edu
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SubjectTerms	Adenocarcinoma of Lung - genetics Animals CD8-Positive T-Lymphocytes Humans Immunity Immunotherapy - methods Lung Neoplasms - pathology Mice
Title	Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma
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