Association of IL-36γ with tertiary lymphoid structures and inflammatory immune infiltrates in human colorectal cancer
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.
KeywordsTertiary lymphoid structure Interleukin (IL)-36 g Colorectal cancer Memory T cells M1 classically activated macrophages
Effector memory T cells that express CD45RA
High endothelial venule
Peripheral node addressin
Alpha-smooth muscle actin
Smooth muscle cells
Central memory T cells
Tertiary lymphoid structures
Vascular endothelial cells
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.
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.
All the included patients signed an informed consent form prior to inclusion in the study.
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