Abstract
Immune checkpoint inhibitors have revolutionized cancer treatment in the last decade. Despite the progress in immunotherapy, most pancreatic cancer patients still do not derive benefit when receiving immune-based therapies. Recently, resistance mechanisms to immune therapies have been mainly focused on tumor microenvironment properties. Pancreatic cancer is considered one of the most lethal and difficult to treat tumors due to its highly immunosuppressive and desmoplastic microenvironment. Low molecular weight heparins (LMWHs) have been used for the treatment and prevention of thromboembolic disease in these patients. However, many nonanticoagulant properties attributed to LMWHs have been described. Exploiting LMWH properties in a combined treatment modality with immune checkpoint inhibition and chemotherapy could provide a new approach in the management of pancreatic adenocarcinoma patients. The ability of LMWH to interfere with various aspects of the tumor microenvironment could result in both the alleviation of immunosuppression and improvement in drug delivery within the tumor, leading to higher cancer cell destruction rates and more potent immune system activity that would, ultimately, lead to better patient outcomes.
Highlights
Cancer therapy has traditionally been based on targeting tumor cells with cytotoxic chemotherapy or radiotherapy, while surgery is the prevailing modality for long-term disease control and cure [1]
Based on the combinatorial therapy approach to treat a highly malignant and refractory cancer such as pancreatic adenocarcinoma (PDAC), we propose that Low molecular weight heparins (LMWHs) could augment the antitumor effectiveness of immune checkpoint inhibitors and chemotherapy, and we outline the potential mechanisms by which this could be achieved
Pancreatic adenocarcinoma remains one of the most challenging neoplasms, exhibiting great treatment hurdles and a dismal long-term overall survival. This is the result of specific features found in PDAC, including a highly desmoplastic stromal tumor microenvironment (TME) that acts by limiting effective drug delivery to malignant cells and by suppressing the host immune system to escape cancer cell elimination
Summary
Cancer therapy has traditionally been based on targeting tumor cells with cytotoxic chemotherapy or radiotherapy, while surgery is the prevailing modality for long-term disease control and cure [1]. The exact mechanism of resistance to immunotherapy is still under investigation, but recent data indicate that the tumor microenvironment plays a major role in establishing immune-suppressive phenotypes, rendering cancers refractory to treatment One such case is pancreatic adenocarcinoma (PDAC), where immunotherapy has shown only minimal benefit in a very small subgroup of patients. LMWHs, such as dalteparin, tinzaparin, and enoxaparin, are anticoagulants that inhibit the final step in the common pathway of the coagulation cascade (they inhibit factor Xa by activating antithrombin III) [10] They constitute the first-line treatment for VTE patients, as they are more beneficial compared to unfractionated heparin, due to the reduced administration frequency that comes as a result of their extended half-lives. Based on the combinatorial therapy approach to treat a highly malignant and refractory cancer such as PDAC, we propose that LMWHs could augment the antitumor effectiveness of immune checkpoint inhibitors and chemotherapy, and we outline the potential mechanisms by which this could be achieved
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