June 19, 2024

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Cell Pyroptosis at the Forefront of Cancer Immunotherapy

Cell Pyroptosis at the Forefront of Cancer Immunotherapy



Cell Pyroptosis at the Forefront of Cancer Immunotherapy

Cell pyroptosis is gaining prominence as a pivotal element in cancer immunotherapy.

Resistance to apoptosis and the immunosuppressive tumor microenvironment are two main factors contributing to poor treatment response in cancer.

Cell pyroptosis, a distinctive and inflammatory form of programmed cell death distinct from apoptosis, has shown promising results in inducing strong inflammatory responses and significant tumor regression in recent studies.

 


Cell Pyroptosis Fundamentals:

Cell pyroptosis is a cell death pathway characterized by the formation of pores, mediated by gasdermin proteins.

These proteins release pro-inflammatory cytokines and immunogenic substances upon cell rupture, facilitating immune cell activation and infiltration.

However, due to its inflammatory nature, aberrant cell pyroptosis may also be associated with the formation of tumor-supportive microenvironments. Understanding the molecular pathways of cell pyroptosis and unraveling its complex connection with cancer can help harness its potential for cancer treatment.

 

Cell Pyroptosis at the Forefront of Cancer Immunotherapy

 

Molecular Mechanisms of Cell Pyroptosis: Currently, there are two main pathways and several alternative pathways of cell pyroptosis. The primary pathways involve GSDMD-mediated cell pyroptosis, mediated by either inflammatory caspase-1 (the classical pathway) or caspase-4/5 (the non-classical pathway). In the alternative pathways, GSDME-mediated cell pyroptosis, induced by caspase-3, has garnered significant attention.

 

 


Inflammasome Pathways:

In the classical inflammasome pathway, pattern recognition receptors (PRRs) recognize damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs), leading to the activation of the inflammasome, a cytosolic signaling complex composed of sensor proteins, adapters, and effector caspases, primarily caspase-1.

Activated PRRs in this subgroup, such as NLRP1, NLRP3, NLRP4, AIM2, and pyrin, interact with the adapter protein ASC, which then recruits and cleaves caspase-1.

In addition to releasing and activating GSDMD, caspase-1 also matures pro-inflammatory cytokines, IL-1β and IL-18, and releases them through the pores formed by GSDMD-N.

 

Cell Pyroptosis at the Forefront of Cancer Immunotherapy

 

Non-Classical Inflammasome Pathway: In the non-classical inflammasome pathway, caspase-4, caspase-5, and mouse caspase-11 are activated by binding to lipopolysaccharides (LPS) and their respective precursor caspases, bypassing the inflammasome sensors. Although these caspases do not directly activate IL-1β and IL-18, they trigger cell pyroptosis by cleaving GSDMD, leading to potassium efflux, NLRP3 inflammasome activation, and upregulation of caspase-1.

 

Alternative Pathways:

Studies suggest that in certain situations, such as chemotherapy or targeted cancer therapy, cell pyroptosis may transition from caspase-3-induced apoptosis to pyroptosis. This transition may depend on the level of GSDME, where higher levels lead to pyroptosis, while lower levels result in apoptosis. Several other alternative pathways of cell pyroptosis involve the cleavage of GSDMD, GSDME, GSDMB, and GSDMC by various caspases or enzymes.

 

Cell Pyroptosis in Cancer and Its Components:

The role of cell pyroptosis in cancer appears to be context-dependent and associated with cell type, genetics, and induction duration. Dysregulated expression and prolonged activity of GSDMs, inflammasomes, and pro-inflammatory cytokines have been linked to tumor promotion, epithelial-mesenchymal transition, and extracellular matrix remodeling. Conversely, cell pyroptosis can also suppress tumors, such as in a liver cancer model, where NLRP3 inflammasome-induced cell pyroptosis significantly inhibits tumor metastasis and growth.

Cell pyroptosis-related components exhibit differential expression and function in different cancer types. GSDMs have been shown to function as oncogenes or tumor suppressors in breast cancer, gastric cancer, cervical cancer, and lung cancer. For example, GSDMD expression is significantly reduced in gastric cancer, leading to enhanced tumor proliferation both in vitro and in vivo. Conversely, GSDMD levels are markedly elevated in non-small cell lung cancer (NSCLC) and are associated with tumor metastasis and a worse prognosis. GSDME expression is reduced in gastric cancer, breast cancer, and colon cancer, while GSDMC is upregulated in colon cancer, promoting carcinogenesis and proliferation. Higher GSDMB levels are associated with increased metastasis and lower survival in breast cancer patients. AIM2 and NLRP1 levels are decreased in colorectal cancer tumors and correlate with poor patient outcomes. Caspase-1 levels are significantly reduced in breast cancer tissues and linked to tumor occurrence in prostate and colon cancer.

The relationship between cell pyroptosis and cancer warrants further extensive research to identify the tumor-specific effects of each cell pyroptosis component. Given the complexity of multiple pathways and overlapping components, characterizing the overall tumor-specific effects of each pathway, rather than individual components, may provide a more effective strategy to understand and predict tumor regulation of cell pyroptosis.

 

Cell Pyroptosis and Anti-Tumor Immunity:

Cell death triggering adaptive immune responses is known as immunogenic cell death (ICD). Unlike apoptosis, which is primarily an immune-tolerant process, cell pyroptosis has molecular mechanisms that induce strong inflammatory responses, making it a potential form of ICD. Although the relationship between cell pyroptosis and anti-cancer immunity is not entirely clear, growing evidence suggests that cell pyroptosis-mediated tumor clearance is achieved through enhanced immune activation and functionality.

 

GSDMA:

Studies have shown that selectively delivering mouse GSDMA3 into human HeLa cells, mouse EMT6 cells, and mouse 4T1 cancer cells led to pyroptosis in 20-40% of the cells. In in vivo models, treatment with NP–Gsdma3 through intravenous or intratumoral injections significantly reduced tumor sizes. Compared to the PBS control group, NP–Gsdma3 treatment increased the number of CD4+, CD8+, natural killer (NK), and M1 macrophages in the tumors. It also decreased the number of monocytes, neutrophils, and M2 macrophages. These results suggest that Gsdma3-induced cell pyroptosis can reprogram the tumor microenvironment by promoting anti-tumor immunity.

Gasdermins:

Gasdermin expression is frequently altered in various cancers. GSDMD, which is commonly overexpressed in lung adenocarcinoma and promotes cell pyroptosis, has been shown to enhance immune responses by recruiting neutrophils and tumor-associated macrophages (TAMs). This recruitment leads to increased levels of TNF-α, IL-6, and IL-1β, stimulating tumor infiltration by cytotoxic T lymphocytes (CTLs). The presence of CTLs and reduced TAMs in tumors can lead to a better prognosis.

GSDME:

GSDME is another gasdermin that has demonstrated a significant role in promoting anti-tumor immunity. While GSDME is typically downregulated in tumor cells, its upregulation can be induced through various mechanisms, such as chemotherapy. The increase in GSDME triggers pyroptosis, releasing pro-inflammatory cytokines and danger signals, further recruiting immune cells. This process stimulates the activation of cytotoxic T lymphocytes (CTLs), dendritic cells, and macrophages, resulting in a potent anti-tumor immune response.

Inflammasomes:

The NLRP3 inflammasome, known to induce cell pyroptosis, plays a role in regulating anti-tumor immunity. In murine models of breast cancer, NLRP3 inflammasome activation led to increased IL-1β production and subsequent recruitment of myeloid-derived suppressor cells (MDSCs). Additionally, studies have suggested that NLRP3 activation may affect the infiltration of CD4+ T cells and CD8+ T cells in the tumor microenvironment.

 

Clinical Implications:

Cell pyroptosis as a cancer immunotherapy strategy is still in its early stages. Several key clinical implications need to be considered:

  1. Personalized Medicine: Tailoring cell pyroptosis-based treatments to specific cancer types, tumor characteristics, and immune profiles is essential to maximize their efficacy.

  2. Combination Therapies: Combining cell pyroptosis inducers with checkpoint inhibitors or other immunotherapies may improve the overall treatment response.

  3. Biomarkers: Identifying reliable biomarkers for predicting the response to cell pyroptosis induction is crucial for patient stratification and treatment monitoring.

  4. Safety Concerns: As cell pyroptosis is associated with inflammation, there may be safety concerns regarding systemic side effects. Careful monitoring and regulation of the therapy are necessary to manage potential toxicities.

 


Conclusion:

Cell pyroptosis is emerging as a novel and promising avenue in cancer immunotherapy. Harnessing the potential of this inflammatory cell death pathway to trigger strong anti-tumor immune responses while minimizing the immunosuppressive tumor microenvironment is a significant research and clinical challenge. Further studies are needed to better understand the context-dependent role of cell pyroptosis in cancer and develop effective therapeutic strategies. Combining cell pyroptosis induction with other immunotherapies holds promise for improving cancer treatment outcomes and expanding the arsenal of tools against this complex disease.

Cell Pyroptosis at the Forefront of Cancer Immunotherapy


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