Apoptosis, Pyroptosis, and Ferroptosis Conspiringly Induce Immunosuppressive Hepatocellular Carcinoma Microenvironment and γδ T-Cell Imbalance

Abstract

Hepatocellular carcinoma (HCC) is highly malignant and prone to metastasize due to the heterogeneous and immunosuppressive tumor microenvironment (TME). Programmed cell deaths (PCDs) including apoptosis, ferroptosis, and pyroptosis routinely occur in the HCC TME and participate in tumorigenesis. However, how apoptosis, ferroptosis, and pyroptosis are involved in constructions of the immunosuppressive TME and their underlying cross-talk remains to be further unveiled. In this work, we deciphered the immunosuppressive landscape of HCC TME, which demonstrated high expressions of inhibitory checkpoint molecules and infiltration of protumor immune cells but low infiltration of antitumor effector immune cells. Further investigations unequivocally revealed that marker genes of apoptosis, ferroptosis, and pyroptosis are closely correlated with expressions and infiltrations of inhibitory checkpoint molecules and immune cells and that higher “-optosis” links to poorer patient prognosis. Notably, such three types of “-optosis” interact with each other at both the gene and protein levels, suggesting that they conspiringly induce the establishment of the immunosuppressive HCC TME. Interestingly, examinations of circulating γδ T cells in HCC patients revealed a noticeable dysfunction phenotype. The strikingly elevated ratio of the Vδ1+ versus the Vδ2+ subset suggested that the Vδ1+/Vδ2+ ratio would be a potential biomarker for the diagnosis and prognosis in HCC patients. Altogether, this work thoroughly decrypted the underlying correlations between apoptosis, ferroptosis, and pyroptosis and the formation of immunosuppressive HCC TME and, meanwhile, indicated that allogeneic Vδ2+ γδ T-cell transfer would be a promising adjuvant strategy for renormalizing circulating γδ T cell and thus achieving sound clinical efficacy against HCC.

Polysaccharide of Atractylodes macrocephala Koidz Alleviates Cyclophosphamide-Induced Thymus Ferroptosis in Gosling

“…However, many studies have found that ferroptosis and apoptosis are closely linked, that apoptosis can be converted into ferroptosis under certain conditions, and that ferroptosis promotes cell sensitivity to apoptosis [ 26 , 27 ]. Hu et al found that apoptosis, pyroptosis, and ferroptosis together induced an immunosuppressive hepatocellular carcinoma microenvironment and γδ T-cell imbalance [ 28 ]. Our HE, TEM, and SEM results showed that CTX causes thymus injury, which is mainly manifested by the indistinct cortex and medullary demarcation of the thymus and reduced cortical thickness.…”

Cell Death in Liver Disease and Liver Surgery

“…In breast cancer, cancer-associated fibroblasts (CAF), another abundant cell type in the TME, facilitate tumor growth and metastasis through inflammasome signaling, a process attenuated when NLRP3 or IL-1β is specifically ablated [ 182 ]. In liver cancer, transcriptomic data from HCC samples indicate a highly immunosuppressive TME and upregulated markers for apoptosis, ferroptosis, and pyroptosis are associated with poorer survival [ 183 ]. However, it remains unclear how pyroptosis precisely affects biological processes in the TME of HCC and contributes to a pro- or anti-immunogenic TME.…”

Role of ferroptosis and its non-coding RNA regulation in hepatocellular carcinoma

“…It not only restrains the activity of antitumor immune cells and compromises the antitumor immunity, but causes the reversal of immunosuppression through the functional regulation of immunosuppressive immune cells ( Cong et al, 2022 ). It is reported that ferroptosis-related genes are associated with infiltration of protumor immune cells and expressions of inhibitory checkpoint molecules, indicating the involvement of ferroptosis in construction of the immunosuppressive TME in HCC ( Hu Y. et al, 2022 ). Similarly, HBV infection facilitates HCC cells to secrete the exosome miR-142-3p, which decreases the expression of SLC3A2 and further induces ferroptosis in M1 macrophages, accelerating the progression of HCC ( Hu Z. et al, 2022 ).…”