The Caspase-1/IL-18 Axis of the Inflammasome in Tumor Cells: A Modulator of the Th1/Tc1 Response of Tumor-Infiltrating T Lymphocytes in Colorectal Cancer

Abstract

In colorectal cancer (CRC), a high density of T lymphocytes represents a strong prognostic marker in subtypes of CRC. Optimized immunotherapy strategies to boost this T-cell response are still needed. A good candidate is the inflammasome pathway, an emerging player in cancer immunology that bridges innate and adaptive immunity. Its effector protein caspase-1 matures IL-18 that can promote a T-helper/cytotoxic (Th1/Tc1) response. It is still unknown whether tumor cells from CRC possess a functional caspase-1/IL-18 axis that could modulate the Th1/Tc1 response. We used two independent cohorts of CRC patients to assess IL-18 and caspase-1 expression by tumor cells in relation to the density of TILs and the microsatellite status of CRC. Functional and multiparametric approaches at the protein and mRNA levels were performed on an ex vivo CRC explant culture model. We show that, in the majority of CRCs, tumor cells display an activated and functional caspase-1/IL-18 axis that contributes to drive a Th1/Tc1 response elicited by TILs expressing IL-18Rα. Furthermore, unsupervised clustering identified three clusters of CRCs according to the caspase-1/IL-18/TIL density/interferon gamma (IFNγ) axis and microsatellite status. Together, our results strongly suggest that targeting the caspase-1/IL-18 axis can improve the anti-tumor immune response in subgroups of CRC.

PDGF-β and IL-18 Expressions on Carcinoma Cervical by Rhodomyrtus tomentosa

“…Due to its immune-stimulating and anti-cancer actions, IL-18 has been proposed as a viable adjuvant therapy for cancer [15][16][17] . However, IL-18 has been linked to the advancement of the disease and in some malignancies, with the likelihood of recurrence and is raised in the blood of the majority of cancer patients [17][18][19] . It is also addressed how Rhodomyrtone, a bioactive substance found in Rhodomyrtus tomentosa leaves, prevents A431 epidermoid carcinoma cells from spreading malignancy 25,26 .…”

“…Casp1 enzymatically processes the inactive precursor (pro-IL-18) into the mature form of IL-18 17 . Through the stimulation of NK and/or T cell responses, IL-18 has been studied in clinical trials on cancer patients and has demonstrated anti-tumour effectiveness in numerous preclinical models of cancer immunotherapy 18,19 .…”

Inflammatory Cytokines Associated with Diagnosis, Tumor Grade and Prognosis in Patients with Neuroendocrine Tumors

“…The pro-tumorigenic role of IL-18 has been well-studied [ 34 , 35 , 36 ], and its high availability in the serum makes it a prime candidate as an indicator for epithelial reaction and metastasis formation [ 37 , 38 , 39 ]. Previous research has already established the role of IL-18 in mediating the Th1/tumor-infiltrating lymphocyte response [ 13 ]. Similarly, high levels of IL-6 in hepatocellular carcinoma correlate with poor survival prognosis and recurrence [ 40 ].…”

“…The caspase-1/IL-18 (IL-1ß) axis has additionally been evaluated in tumor-related disease. A recent study has shown that IL-18 correlates with the local Th1/tumor-infiltrating lymphocyte response in colorectal [ 13 ] as well as in breast cancer [ 14 ]. Moreover, it could be shown that the neutrophil-to-lymphocyte ratio and C-reactive protein [ 15 , 16 ], as well as other inflammatory cytokines, are regulated in the environment of neuroendocrine tumors [ 17 ].…”

Inflammasomes and Colorectal Cancer

“…Furthermore, a study by Mutala et al (2021) reported that tumor cells of most CRCs display a functional and activated caspase-1/IL-18 axis that can modulate the IFN-γ response elicited by the Th1/Tc1 response. Moreover, the authors strongly suggested that targeting the inflammasome pathway could improve the antitumor immune response in subgroups of CRC [ 143 ]. Another study reported that the inhibition of NLRP3 inflammasome assembly in macrophages was responsible for the preventive effect of arctigenin against CAC in patients with colitis [ 144 ].…”