Targeting the Interplay of Independent Cellular Pathways and Immunity: A Challenge in Cancer Immunotherapy

Abstract

Immunotherapy is a cancer treatment that exploits the capacity of the body's immune system to prevent, control, and remove cancer. Immunotherapy has revolutionized cancer treatment and significantly improved patient outcomes for several tumor types. However, most patients have not benefited from such therapies yet. Within the field of cancer immunotherapy, an expansion of the combination strategy that targets independent cellular pathways that can work synergistically is predicted. Here, we review some consequences of tumor cell death and increased immune system engagement in the modulation of oxidative stress and ubiquitin ligase pathways. We also indicate combinations of cancer immunotherapies and immunomodulatory targets. Additionally, we discuss imaging techniques, which are crucial for monitoring tumor responses during treatment and the immunotherapy side effects. Finally, the major outstanding questions are also presented, and directions for future research are described.

Keywords: cancer; immunotherapy; immunotherapy-challenges; immunotherapy-limitations.

Figure 3

General scheme of biomarkers for response to immunotherapy. Several predictive biomarkers have been widely investigated for immunotherapy response, but currently, only a few tumor-agnostic biomarkers are FDA-approved (e.g., mismatch repair deficient tumor, dMMR). Despite many options available for immunotherapy (PDL1/PD-1, CTLA-4, LAG-3/TIGIT, CAR T cells, TCR T cells, BiTEs, etc.), there is still no evidence to help us choose which one deserves priority for clinical trials.

Figure 4

Redox signaling signature in the tumor microenvironment (TME). ROS modulation represents a promising strategy in cancer immunotherapy, but to boost ROS-based cancer immunotherapy, several aspects must be investigated. The cartoon highlights the crucial factors to be considered to exploit ROS to improve immunotherapy sensitivity. ROS—reactive oxygen species; H₂O₂—hydrogen peroxide.

Figure 5

General scheme of ubiquitin signaling–TME interplay. Ubiquitin signaling is involved in several aspects of the tumor microenvironment (TME), and its dysregulation may contribute to tumor progression. Therefore, targeting ubiquitin signaling can be a promising therapeutic strategy for cancer treatment. A small molecule named proteolysis targeting chimera (PROTAC) has been approved by the FDA. These small molecules have several advantages, including good solubility and cell permeability. However, the specific role of ubiquitin signaling in the immune system is still unclear, so the interplay of the ubiquitin system and TME deserves more investigations in the future.

Figure 6

Imaging technology in cancer immunotherapy. Imaging techniques are crucial for monitoring tumor responses during treatment. However, despite the explosion of immune-oncological drugs in the past decade, there are several limitations to this strategy: (1) The development of clinical imaging biomarkers for anti-cancer immunotherapy is not keeping up with the speed of immunotherapy development; (2) the spatial resolution of clinical cameras/scanners depends on the radioisotopes’ positron range; and (3) the need to test new markers on animal models with different genetic makeup and immune systems than humans prevents a clear understanding of the tumor microenvironment at the cellular and subcellular levels. Exosomes are nano-sized extracellular vesicles secreted by most cells in the body and carry a range of functional molecules. For example, exosomes have been found to play a pivotal role in cytokine release in CAR-T cell therapy. Scale bar, 20 nm.

Figure 7

General scheme of the microbiota as a mediator of the response to cancer immunotherapy. Several pre-clinical and clinical studies shed light on the role of the microbiota as a mediator of the response to cancer therapy, including cancer immunotherapy. From these studies emerged critical questions: (1) The need for microbiome profiling in patients in cancer therapy (which sequencing methods and which reference databases should we use?). (2) How medications, diet, and environmental factors (factors affecting the gut microbiome) may affect cancer immunotherapy? (3) What is the optimal composition of the gut microbiome to facilitate immune responses? (4) Which options we should use to modulate the gut microbiome to facilitate immune responses?

Figure 8

Cancer vaccine: where are we? Many challenges need to be faced when making cancer vaccines. Some challenges have already been overcome thanks to the discovery of specific tumor antigens and the ability to target them. Still, other challenges need to be addressed: (1) the time the clinical trial takes to test a vaccine; (2) the time needed to develop vaccines specific to different types of tumors. Recently, cancer vaccines have made significant advances. The speed-up of mRNA technology development has turned the standard vaccine timeline into one that is faster and more functional.

Figure 1

Different effects of photodynamic therapy (PDT) on ROS levels in normal and tumor cells. Normal cells have a basal level of ROS (radical oxygen species) required for cell survival and redox signaling. The production of ROS is elevated in tumor cells. When ROS reaches threshold levels, it is able to trigger cell death (the gate toward death). PDT is ROS-based therapy to increase ROS levels in tumor cells so they can reach the death threshold earlier. This therapy is enhanced in combination with immunotherapy.

Figure 2

(A) Immuno-gold transmission electron microscopy analysis of extracellular vesicles isolated from plasma, immune-labeled with a 5 nm gold antibody. Scale bar, 20 nm. (B) 3D-STORM reconstruction with x, y, z coordinates of single-molecule localization within the TIRF plan for a 3D view of a plasma-recovered exosome immune-labeled with Alexa fluor 647. Single molecules are shown on a pseudo-color scale. Scale bar, 20 nm.