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.
['Weinstein|Aliyah M|AM|http://orcid.org/0000-0002-8556-3616', 'Giraldo|Nicolas A|NA|', 'Petitprez|Florent|F|http://orcid.org/0000-0002-5117-6466', 'Julie|Catherine|C|', 'Lacroix|Laetitia|L|', 'Peschaud|Frédérique|F|', 'Emile|Jean-François|JF|http://orcid.org/0000-0002-6073-4466', 'Marisa|Laetitia|L|', 'Fridman|Wolf H|WH|http://orcid.org/0000-0002-1332-0973', 'Storkus|Walter J|WJ|http://orcid.org/0000-0001-8961-4444', 'Sautès-Fridman|Catherine|C|http://orcid.org/0000-0003-1735-8722']
D000368:Aged D000369:Aged, 80 and over D015496:CD4-Positive T-Lymphocytes D015179:Colorectal Neoplasms D005260:Female D020869:Gene Expression Profiling D015972:Gene Expression Regulation, Neoplastic D006801:Humans D007249:Inflammation D007375:Interleukin-1 D008297:Male D008875:Middle Aged D000072717:Tertiary Lymphoid Structures D059016:Tumor Microenvironment
Tertiary lymphoid structure Colorectal cancer Memory T cells Interleukin (IL)-36 g M1 classically activated macrophages