The visual below illustrates the combined or synergistic effects of Hyperthermia Therapy (HT) and Chemotherapy (CT) on tumors. This comprehensive view is broken down into several subpanels, each providing a more detailed look at the pleiotropic effects of these therapies, which can be explored further in this blog.
The systemic effects of hyperthermia on the vasculature are highlighted in the image below. Pancreatic ductal adenocarcinoma (PDAC) is often hypoxic, making it more aggressive, resistant to systemic therapies, and evasive to the immune system. Hyperthermia helps alleviate hypoxia by inducing vasodilatation, increasing perfusion, permeability, and re-oxygenation. This improvement in blood flow decreases therapy resistance and enhances the immune system’s ability to access and attack the tumor through better-perfused vessels.
On the image below, we see the cellular effects of hyperthermia and chemotherapy compounds. Here, several possible synergisms between hyperthermia and chemotherapy are indicated, shown by flame symbols paired with chemotherapy symbols. The figure depicts a close-up of a cell, with the membrane on the left, separating the cell from the outside, and the cytosol and nucleus on the inside.
First, let’s look at the effects of hyperthermia and oxaliplatin (OX), a crosslinking chemotherapy agent. OX can induce mitochondrial stress and possibly crosslink ribosomal or ER proteins, inducing stress in the endoplasmic reticulum (ER). Hyperthermia , in turn, induces reactive oxygen species (ROS), which also stress the mitochondria. This cellular stress is crucial as it can trigger regulated cell death, an anti-tumor mechanism.
Within the nucleus, the cell cycle is depicted, showing how chemotherapy compounds and hyperthermia affect it. Paclitaxel (blue) impacts the M-phase by interfering with the formation of the mitotic spindle, necessary for DNA division during cell replication. Own research (data not published) indicates that hyperthermia disrupts the M-phase, suggesting a synergy between paclitaxel and hyperthermia that could halt cell division completely.
Gemcitabine (brown, GEM) is effective during the S-phase, where DNA replication occurs. GEM, as a base analog, incorporates faulty bases into the DNA, halting replication. Own research (data not published) shows that hyperthermia prolongs the S-phase, synchronizing cells in this stage. Thus, scheduling GEM in relation to hyperthermia is vital for maximizing their synergistic effect.
Under hyperthermia conditions, OX is expected to accumulate more within the cell, enhancing DNA crosslinking. Throughout the cell cycle, several checkpoints ensure proper progression. Chemotherapy /hyperthermia effects can trigger cell cycle breaks at these checkpoints, steering the cell towards death. Hyperthermia also compromises the cell’s repair mechanisms, increasing the likelihood of cell death due to accumulated damage.
The top right panel illustrates the significantly boosted anti-tumor immune response due to hyperthermia. We see the immune cascade starting from the detection of PDAC cells by antigen-presenting cells (APCs), like dendritic cells (DCs), which mature and trigger responses from natural killer (NK) cells and T-helper (CD4+) and cytotoxic (CD8+) T cells. CD4+ T cells activate macrophages and secrete pro-inflammatory cytokines.
Literature indicates that hyperthermia enhances the homing of cytotoxic T cells and major histocompatibility complex (MHC) expression, increasing cancer cell eradication. The death of cancer cells releases their contents into the tumor microenvironment, further activating the immune system, a phenomenon known as immunogenic cell death—a key focus of ElmediX’s research.
Mechanisms of immunogenic cell death
The last image delves into the mechanisms of immunogenic cell death. Several danger signaling molecules are involved in this process, induced by oxaliplatin and likely paclitaxel. Hyperthermia also influences the induction of danger-associated molecular patterns (DAMPs), such as heat shock proteins (HSPs), HMGB1, surface calreticulin (CRT), and ATP release. These DAMPs are crucial for initiating immunogenic cell death, leading to a cascade of immune activation and tumor-specific cell death.
At ElmediX, we are dedicated to further exploring hyperthermia and its mechanisms, leveraging these insights to develop more effective cancer therapies.
ElmediX strives to extend the lives of cancer patients worldwide and to improve their quality of life. Initially, our focus is on pancreatic cancer, but other cancer types are also being investigated.