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Infiltration of NK and plasma cells is associated with a distinct immune subset in non-small cell lung cancer

Backman, Max ; La Fleur, Linnéa ; Kurppa, Pinja ; Djureinovic, Dijana ; Elfving, Hedvig ; Brunnström, Hans LU orcid ; Mattsson, Johanna Sofia Margareta ; Lindberg, Amanda ; Pontén, Victor and Eltahir, Mohamed , et al. (2021) In Journal of Pathology 255(3). p.243-256
Abstract

Immune cells of the tumor microenvironment are central but erratic targets for immunotherapy. The aim of this study was to characterize novel patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to its molecular and clinicopathologic characteristics. Lymphocytes (CD3+, CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+), PD1+, and PD-L1+ were annotated on a tissue microarray including 357 NSCLC cases. Somatic mutations were analyzed by targeted sequencing for 82 genes and a tumor mutational load score was estimated. Transcriptomic immune patterns were established in 197 patients based on RNA sequencing data. The immune cell infiltration was variable and... (More)

Immune cells of the tumor microenvironment are central but erratic targets for immunotherapy. The aim of this study was to characterize novel patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to its molecular and clinicopathologic characteristics. Lymphocytes (CD3+, CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+), PD1+, and PD-L1+ were annotated on a tissue microarray including 357 NSCLC cases. Somatic mutations were analyzed by targeted sequencing for 82 genes and a tumor mutational load score was estimated. Transcriptomic immune patterns were established in 197 patients based on RNA sequencing data. The immune cell infiltration was variable and showed only poor association with specific mutations. The previously defined immune phenotypic patterns, desert, inflamed, and immune excluded, comprised 30, 13, and 57% of cases, respectively. Notably, mRNA immune activation and high estimated tumor mutational load were unique only for the inflamed pattern. However, in the unsupervised cluster analysis, including all immune cell markers, these conceptual patterns were only weakly reproduced. Instead, four immune classes were identified: (1) high immune cell infiltration, (2) high immune cell infiltration with abundance of CD20+ B cells, (3) low immune cell infiltration, and (4) a phenotype with an imprint of plasma cells and NK cells. This latter class was linked to better survival despite exhibiting low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, CTLA4). This compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC reveals two previously unrecognized immune classes. A refined immune classification, including traits of the humoral and innate immune response, is important to define the immunogenic potency of NSCLC in the era of immunotherapy.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
checkpoint therapy, immune cell infiltration, lung cancer, NSCLC, p53, PD-L1, tumor microenvironment
in
Journal of Pathology
volume
255
issue
3
pages
243 - 256
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:85113394982
  • pmid:34339045
ISSN
0022-3417
DOI
10.1002/path.5772
language
English
LU publication?
yes
id
e4a1d299-c87c-4000-959e-38add72422d6
date added to LUP
2021-09-09 13:45:17
date last changed
2024-06-15 16:03:41
@article{e4a1d299-c87c-4000-959e-38add72422d6,
  abstract     = {{<p>Immune cells of the tumor microenvironment are central but erratic targets for immunotherapy. The aim of this study was to characterize novel patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to its molecular and clinicopathologic characteristics. Lymphocytes (CD3+, CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+), PD1+, and PD-L1+ were annotated on a tissue microarray including 357 NSCLC cases. Somatic mutations were analyzed by targeted sequencing for 82 genes and a tumor mutational load score was estimated. Transcriptomic immune patterns were established in 197 patients based on RNA sequencing data. The immune cell infiltration was variable and showed only poor association with specific mutations. The previously defined immune phenotypic patterns, desert, inflamed, and immune excluded, comprised 30, 13, and 57% of cases, respectively. Notably, mRNA immune activation and high estimated tumor mutational load were unique only for the inflamed pattern. However, in the unsupervised cluster analysis, including all immune cell markers, these conceptual patterns were only weakly reproduced. Instead, four immune classes were identified: (1) high immune cell infiltration, (2) high immune cell infiltration with abundance of CD20+ B cells, (3) low immune cell infiltration, and (4) a phenotype with an imprint of plasma cells and NK cells. This latter class was linked to better survival despite exhibiting low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, CTLA4). This compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC reveals two previously unrecognized immune classes. A refined immune classification, including traits of the humoral and innate immune response, is important to define the immunogenic potency of NSCLC in the era of immunotherapy.</p>}},
  author       = {{Backman, Max and La Fleur, Linnéa and Kurppa, Pinja and Djureinovic, Dijana and Elfving, Hedvig and Brunnström, Hans and Mattsson, Johanna Sofia Margareta and Lindberg, Amanda and Pontén, Victor and Eltahir, Mohamed and Mangsbo, Sara and Gulyas, Miklos and Isaksson, Johan and Jirström, Karin and Kärre, Klas and Leandersson, Karin and Mezheyeuski, Artur and Pontén, Fredrik and Strell, Carina and Lindskog, Cecilia and Botling, Johan and Micke, Patrick}},
  issn         = {{0022-3417}},
  keywords     = {{checkpoint therapy; immune cell infiltration; lung cancer; NSCLC; p53; PD-L1; tumor microenvironment}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{243--256}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Journal of Pathology}},
  title        = {{Infiltration of NK and plasma cells is associated with a distinct immune subset in non-small cell lung cancer}},
  url          = {{http://dx.doi.org/10.1002/path.5772}},
  doi          = {{10.1002/path.5772}},
  volume       = {{255}},
  year         = {{2021}},
}