Leveraging immunogenic cell death in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) remains the most aggressive and deadly type of cancer, with a five-year survival rate of merely 11%. By 2030, PDAC is projected to become the second leading cause of cancer mortality in the United States. Standard treatments, including radical surgery and adjuvant chemotherapy, offer long-term survival for only a minority of patients, as most are diagnosed at an advanced stage where surgery is no longer viable. Current therapies, primarily cytotoxic chemotherapy combined with supportive care, are hampered by significant side effects and limited overall response rates. Therefore, exploring new therapeutic approaches is imperative.

Immunotherapy, which has shown remarkable success across various solid tumors, has been less effective for PDAC due to its unique histopathological characteristics. The low tumor mutational burden in pancreatic cancer leads to minor antigenicity, and the dense extracellular matrix along with the poorly formed vascular system hinders immune cell infiltration. This creates an "immune-excluded" tumor microenvironment (TME) that is incapable of eliciting a strong immune response. Innovative strategies are needed to overcome these barriers and develop effective treatments for PDAC.

Immunogenic Cell Death (ICD) in PDAC

Immunogenic cell death (ICD) is a form of programmed cell death that triggers an immune response by releasing damage-associated molecular patterns (DAMPs). ICD provides ample antigens to compensate for the low immunogenicity of pancreatic cancer and mobilizes the immune system, transforming the "cold" TME into an immune-reactive state, thereby initiating an anti-tumor immune response and leading to tumor regression. Traditional PDAC therapies have shown some antitumor effects through ICD, and understanding ICD has led to the development of novel agents for PDAC immunotherapy. Inducing ICD appears to be a promising strategy for enhancing immunochemotherapy for PDAC.

Paradigm of ICD

Cell death is generally classified into apoptosis, considered physiological and immuno-tolerogenic, and necrosis, viewed as pathological and immunogenic. ICD, a variant of apoptosis, can generate cancer vaccines and stimulate antineoplastic immune responses. Various factors, including viral infections, stress, therapeutic drugs, radiation therapy, and some physical therapies, can initiate ICD by causing endoplasmic reticulum stress (ERS), which produces reactive oxygen species (ROS) and host-derived immune-activating molecules like DAMPs. These molecules, detected by pattern recognition receptors (PRRs) on innate immune cells, trigger an adaptive immune response, ultimately leading to the recruitment of effective T cells and long-term immunologic memory.

Prerequisites of ICD: Antigenicity and Adjuvanticity

ICD requires antigenicity and adjuvanticity. Antigenicity involves tumor-associated antigens (TAA) and tumor neoantigens (TNA) presented through MHC-II molecules, which are distinct from normal peptides. The release or presentation of these antigens during cell death provides the necessary antigenicity for ICD. Adjuvanticity, defined by DAMPs, simplifies its molecular characterization. Early release of ATP binds to P2RY2 on DCs or macrophages, emitting a "find me" signal, followed by calreticulin (CALR) translocation to the cell surface, emitting an "eat me" signal. HMGB1 further promotes DC maturation and antigen presentation, leading to effector T cell recruitment and memory T cell production. These clear immune molecules are more manipulable and druggable than complex peptide chains.

DAMPs of ICD

DAMPs are molecules released in response to cellular stress, recognized by innate immune cells through PRRs, triggering immune responses. The canonical DAMPs in ICD include CALR, extracellular ATP, and HMGB1.

CALR translocates from the ER to the plasma membrane during ICD, serving as an "eat-me" signal for DCs, aiding in the engulfment of dying cells. This process involves phosphorylation of eIF2α, activation of caspase 8, cleavage of BCAP31, aggregation of BAX and BAK1, and transport of CALR to the cell surface along with ERp57. CALR binds to CD91 on antigen-presenting cells, promoting cellular corpse engulfment, and enhancing immunity by improving IL-15 trans-presentation to NK cells.

HMGB1 is released during ICD when the nuclear lamina and plasma membrane become permeable. It interacts with TLR2, TLR4, and RAGE, promoting antigen presentation and DC maturation. HMGB1's immunostimulatory function depends on its redox state, with ROS-induced oxidation limiting its activity.

ATP is released through pannexin channels and exocytosis during ICD, acting as a "find-me" signal for immune cells, further enhancing the immune response.

Strategies to Induce ICD in PDAC

Recent research has focused on various strategies to induce ICD in PDAC to overcome its resistance to immunotherapy. These strategies include chemotherapeutic agents, oncolytic viruses, photodynamic therapy (PDT), and radiation therapy.

Chemotherapeutic agents like anthracyclines have shown potential in inducing ICD. These drugs cause ER stress and ROS production, leading to DAMP release and subsequent immune activation. Combining chemotherapeutic agents with immune checkpoint inhibitors can further enhance the anti-tumor immune response.

Oncolytic viruses selectively infect and kill cancer cells while sparing normal tissues. These viruses can induce ICD by causing ER stress and promoting the release of DAMPs. Additionally, oncolytic viruses can be engineered to express immune-stimulatory molecules, further enhancing the immune response against the tumor.

Photodynamic therapy (PDT) involves the administration of a photosensitizer followed by light exposure, generating ROS and causing cell death. PDT has been shown to induce ICD in various cancers, including PDAC. The combination of PDT with immune checkpoint inhibitors or other immunotherapies can potentiate the anti-tumor immune response.

Radiation therapy has been a standard treatment for various cancers and can induce ICD by causing DNA damage and ER stress. Combining radiation therapy with immunotherapy can enhance the anti-tumor immune response by increasing the infiltration of immune cells into the tumor microenvironment.

Clinical Implications and Future Directions

The induction of ICD in PDAC holds significant promise for improving the efficacy of immunotherapy. Clinical trials exploring combinations of ICD-inducing agents with immune checkpoint inhibitors, adoptive cell therapy, and other immunotherapies are ongoing. The success of these trials could pave the way for new therapeutic strategies that transform PDAC from an immune-excluded to an immune-reactive disease.

Future research should focus on identifying the most effective combinations of ICD inducers and immunotherapies, understanding the mechanisms underlying ICD, and developing biomarkers to predict response to treatment. Personalized approaches that consider the unique characteristics of each patient's tumor and immune system will be crucial in optimizing the efficacy of ICD-based therapies.

Conclusions

ICD represents a promising strategy for overcoming the immune-suppressed TME of PDAC. By inducing ICD, it is possible to turn "cold" tumors into "hot" ones, enhancing the efficacy of immunotherapies. The manipulation of ICD inducers can synergize with other treatments, potentially leading to significant advances in the treatment of pancreatic cancer. Clinical trials based on this strategy may offer new hope for patients with this challenging disease. As our understanding of ICD and its role in cancer immunotherapy deepens, it will be essential to translate these insights into clinical practice to improve outcomes for patients with PDAC.

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https://www.xiahepublishing.com/2835-3315/CSP-2023-00015

The study was recently published in the Cancer Screening and Prevention.

Cancer Screening and Prevention (CSP) publishes high-quality research and review articles related to cancer screening and prevention. It aims to provide a platform for studies that develop innovative and creative strategies and precise models for screening, early detection, and prevention of various cancers. Studies on the integration of precision cancer prevention multiomics where cancer screening, early detection and prevention regimens can precisely reflect the risk of cancer from dissected genomic and environmental parameters are particularly welcome.

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