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Association of IL-36γ with tertiary lymphoid structures and inflammatory immune infiltrates in human colorectal cancer

  • Aliyah M. Weinstein
  • Nicolas A. Giraldo
  • Florent Petitprez
  • Catherine Julie
  • Laetitia Lacroix
  • Frédérique Peschaud
  • Jean-François Emile
  • Laetitia Marisa
  • Wolf H. Fridman
  • Walter J. Storkus
  • Catherine Sautès-Fridman
Original Article

Abstract

IL-1 family cytokines play a dual role in the gut, with different family members contributing either protective or pathogenic effects. IL-36γ is an IL-1 family cytokine involved in polarizing type-1 immune responses. However, its function in the gut, including in colorectal cancer pathogenesis, is not well appreciated. In a murine model of colon carcinoma, IL-36γ controls tertiary lymphoid structure formation and promotes a type-1 immune response concurrently with a decrease in expression of immune checkpoint molecules in the tumor microenvironment. Here, we demonstrate that IL-36γ plays a similar role in driving a pro-inflammatory phenotype in human colorectal cancer. We analyzed a cohort of 33 primary colorectal carcinoma tumors using imaging, flow cytometry, and transcriptomics to determine the pattern and role of IL-36γ expression in this disease. In the colorectal tumor microenvironment, we observed IL-36γ to be predominantly expressed by M1 macrophages and cells of the vasculature, including smooth muscle cells and high endothelial venules. This pattern of IL-36γ expression is associated with a CD4+ central memory T cell infiltrate and an increased density of B cells in tertiary lymphoid structures, as well as with markers of fibrosis. Conversely, expression of the antagonist to IL-36 signaling, IL-1F5, was associated with intratumoral expression of checkpoint molecules, including PD-1, PD-L1, and CTLA4, which can suppress the immune response. These data support a role for IL-36γ in the physiologic immune response to colorectal cancer by sustaining inflammation within the tumor microenvironment.

Keywords

Tertiary lymphoid structure Interleukin (IL)-36 g Colorectal cancer Memory T cells M1 classically activated macrophages 

Abbreviations

EMRA

Effector memory T cells that express CD45RA

HEV

High endothelial venule

IHC

Immunohistochemistry

IM

Invasive margin

MSI

Microsatellite instable

PNAd

Peripheral node addressin

SMA

Alpha-smooth muscle actin

SMC

Smooth muscle cells

TC

Tumor core

TCM

Central memory T cells

TLS

Tertiary lymphoid structures

VEC

Vascular endothelial cells

Notes

Author contributions

AMW, NAG, WHF, and CS-F designed experiments. AMW, NAG, LL, and LM performed experiments. AMW, NAG, FP, WHF, and CS-F analyzed data. AMW, NAG, WHF, WJS, and CS-F wrote the manuscript. FP, CJ and J-FE designed clinical protocol and acquired clinical samples. All authors approved the final version of this manuscript.

Funding

This work was supported by the Institut National de la Santé et de la Recherche Médicale, the University Paris-Descartes, the University Pierre et Marie Curie, Labex Immuno-Oncology (LAXE62_9UMRS972 FRIDMAN) and Cancer Research for Personalized Medecine programmes (CARPEM T8), and grants from Institut du Cancer (INCa) HTE Plan Cancer (C1608DS) and NIH RO1s CA169118 and CA204419. Aliyah M. Weinstein was supported by a Chateaubriand Fellowship of the Office for Science and Technology of the Embassy of France in the United States and Florent Petitprez by CARPEM doctorate fellowship.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval and ethical standards

The research project “Reincolon” was approved by the Institutional Review Board of Hôpitaux Universitaires Paris-Ile de France Ouest-Ambroise Paré (IO-ACA-CRB-FM002). The study was conducted according to the recommendations in the Helsinki Declaration.

Informed consent

All the included patients signed an informed consent form prior to inclusion in the study.

Supplementary material

262_2018_2259_MOESM1_ESM.pdf (10.5 mb)
Supplementary material 1 (PDF 10745 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.INSERM, UMR_S 1138, Cordeliers Research Center, Team “Cancer, Immune Control and Escape”ParisFrance
  2. 2.University Paris Descartes, Paris 5, Sorbonne Paris Cite, UMR_S 1138, Centre de Recherche des CordeliersParisFrance
  3. 3.Sorbonne University, UMR_S 1138, Centre de Recherche des CordeliersParisFrance
  4. 4.Laboratoire d’anatomie pathologiqueHopital Ambroise Paré, AP-HPBoulogneFrance
  5. 5.Programme Cartes d’Identités des TumeursLigue Nationale contre le CancerParisFrance
  6. 6.EA4340Université de Versailles SQY, Université Paris SaclayBoulogneFrance
  7. 7.Department of DermatologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  8. 8.Department of ImmunologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  9. 9.Department of PathologyUniversity of Pittsburgh Cancer Institute, University of Pittsburgh School of MedicinePittsburghUSA
  10. 10.Department of BioengineeringUniversity of Pittsburgh Cancer Institute, University of Pittsburgh School of MedicinePittsburghUSA
  11. 11.Pathology DepartmentJohns Hopkins HospitalBaltimoreUSA

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