- Cancer is the result of a battle between tumor cells and the body’s immune system. Tumor-specific immunotherapy is a critical approach in combating cancer. Current biomarkers can only detect the characteristics of tumor cells, while methods to assess the strength of tumor-specific immunity are still under development. Most immunotherapies work by activating the patient’s existing effector tumor antigen-specific T cells (ETASTs) or stimulating the generation of new ETASTs. Therefore, the quantity of ETASTs can serve as a marker for immune therapy efficacy. Due to the high heterogeneity of tumor antigens and the inability to differentiate ETASTs from other T cells based on structural features, detecting ETASTs has been challenging. However, nanoparticles loaded with whole-cell tumor antigens can specifically activate and detect ETASTs in the blood. This works because ETASTs are activated T cells, whereas other T cells remain in an inactive state. By detecting markers of activation and cytotoxic function, the difference between ETASTs and other T cells can be identified, distinguishing activated from non-activated states. The quantity of ETASTs in the blood of cancer patients is higher than in healthy individuals, and the therapeutic effect correlates positively with the amount of ETASTs in the blood. When immunotherapy takes effect, the levels of ETASTs in the blood increase. Single-cell sequencing results can confirm this conclusion.
- On November 5, 2024, a research paper titled Efficient Predictor for Immunotherapy Efficacy: Detecting Pan-Clones Effector Tumor Antigen-Specific T Cells in Blood by Nanoparticles Loading Whole Tumor Antigens was published online in Advanced Science by the team of Jun Zhao, Mi Liu, Tong Xin, and others from Soochow University. On November 19, 2024, another paper titled Efficient Biomarker for Immunotherapy: Measuring Broad Clones Effector Tumor Antigen-Specific T Cells in the Blood of Esophageal Cancer Patients was published online in Analytical Chemistry. These two papers explored the role of ETAST biomarkers using nanoparticles loaded with whole-cell tumor antigens in both lung and esophageal cancers.
- This research presents a highly accurate and unique biomarker to detect immunotherapy efficacy in cancer patients, which does not require physical interaction with the human body. This biomarker can also be used to assess the effectiveness of other treatment modalities such as radiotherapy, oncolytic virus therapy, and nanoparticle-based treatments.
- Lung cancer is one of the most prevalent and deadly malignancies globally, including adenocarcinoma and squamous cell carcinoma, with non-small cell lung cancer (NSCLC) being predominant. Esophageal cancer includes adenocarcinoma and squamous cell carcinoma, and its progression is rapid. Traditional treatments such as surgery, chemotherapy, and radiotherapy often have limited effects on improving the prognosis of NSCLC and esophageal cancer. Recently, the rapid development of immune checkpoint inhibitors (ICIs) has introduced new treatment options for NSCLC and esophageal cancer. ICIs mainly block the interaction between inhibitory receptors on T cells and their corresponding ligands, thereby regulating immune cell activity and activating and expanding tumor-specific T cell subsets in the patient’s body. The main approach for treating NSCLC and esophageal cancer currently involves inhibiting programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1), which can be used alone or in combination with chemotherapy, and has become the primary treatment for advanced NSCLC patients. However, ICI therapy benefits only a small portion of NSCLC patients and does not benefit the majority. Therefore, identifying effective biomarkers for predicting immunotherapy responses is critical.
- Cancer is the result of the fight between cancer cells and the body’s immune system (primarily tumor-specific T cells). To transform cancer into a chronic or non-fatal disease, immunotherapy must enhance the patient’s tumor-specific immune response. Biomarkers reported thus far have focused on evaluating tumor cell characteristics, including PD-L1 expression levels, tumor mutational burden (TMB), tumor-infiltrating lymphocyte (TIL) counts, and neoantigen load. There has been no systematic use of biomarkers to assess the tumor-specific immune response in cancer patients. Evaluating and demonstrating the tumor-specific immune capacity is beneficial to both physicians and patients.
- Although the FDA has approved the use of PD-L1 expression levels in NSCLC tumor tissue to screen patients for ICI treatment, the diagnostic effectiveness of this biomarker has not met expectations. The limitations of this biomarker mean that relying solely on PD-L1 expression as a screening criterion may exclude some patients who could benefit from ICI therapy, while others who would not benefit might be included. Additionally, multiple studies have shown that specific T cell subsets in tumor tissue (i.e., tumor antigen-specific T cells, TASTs) serve as predictive biomarkers for immunotherapy response. These T cells can specifically recognize tumor antigens, but not all T cells exhibit cytotoxic functionality after recognizing antigens. Specific recognition of tumor antigens can be seen as structural specificity, while the ability to kill antigen-bearing cancer cells after recognition can be seen as functional specificity.
- According to structural and functional specificity, TASTs can be classified into three categories: 1) effector tumor antigen-specific T cells (ETASTs), which can specifically recognize and kill cancer cells containing the antigen; 2) regulatory tumor antigen-specific T cells (RTASTs), which not only specifically recognize tumor antigens but also suppress the function of ETASTs, promoting tumor cell proliferation; 3) non-reactive tumor antigen-specific T cells (ATASTs), which can recognize tumor antigens but lack cytotoxicity after recognition. Recent studies have shown that the types and quantities of ETASTs in cancer patients' blood or peripheral blood after immunotherapy are positively correlated with prognosis. ETASTs are the key force in killing cancer cells and are considered the true participants in immunotherapy. A successful immunotherapy depends on the reactivation of ETASTs. Detecting ETASTs in peripheral blood may become an ideal biomarker to reflect the efficacy of immunotherapy.
- Immunotherapy relies on enhancing the tumor-specific immune response. Accurately detecting pan-clonal ETASTs in peripheral blood is one of the best methods for evaluating the tumor-specific immune response of patients, but this remains a significant challenge. Tumor antigens are diverse, and a single TAST clone can recognize only one tumor antigen, so there are thousands of different TAST clones. According to the theory of tumor immune circulation, after tumor antigens activate TASTs in draining lymph nodes, TASTs enter the tumor tissue through the bloodstream. Thus, blood is the best source for detecting ETASTs. However, the number of ETASTs in the blood is rare and highly heterogeneous, making it challenging to accurately detect all ETASTs using ELISPOT or tetramer technologies. ETASTs are difficult to differentiate from other T cells because TCRs recognize different antigen peptides, especially when identifying all the different ETAST clones. Currently, detecting a few specific ETAST clones is mainly done through multimer technology or ELISPOT, but these methods can only detect T cells that recognize specific antigens. However, these methods are limited to detecting a few peptide antigens, are inaccurate, and are costly, making them unsuitable for widespread clinical use. Therefore, there is an urgent need for a non-invasive, simple, and effective method for detecting ETASTs in peripheral blood.
- The high heterogeneity of tumor cells and tumor antigens makes it difficult to detect pan-clonal ETASTs (all or most clones). Currently, there is no effective method to comprehensively and accurately detect pan-clonal ETASTs in blood, thus failing to provide cancer patients with accurate information about their tumor-specific immune response. This study suggests that nanoparticles loaded with whole tumor antigens (NPs) can effectively recognize pan-clonal ETASTs in peripheral blood mononuclear cells (PBMCs), providing doctors and cancer patients with accurate information about the tumor-specific immune response. When NPs are co-cultured with PBMCs, they are engulfed by antigen-presenting cells (APCs) in the PBMCs, releasing the tumor antigens. The released antigens are degraded into antigen peptides on the surface of the APCs. These peptides can then reactivate the TASTs originally activated by tumor antigens in the draining lymph nodes. Dendritic cells (DCs) are the only APCs capable of activating naive T cells in lymph nodes, while B cells, macrophages, and DCs serve as APCs for the secondary activation of pre-existing non-naive T cells in peripheral tissues or in vitro (Figure 2). When the initial T cells are activated by APCs in the lymph nodes through tumor antigens and transformed into ETASTs, three signals are required: antigen peptide (signal 1), co-stimulatory molecules (signal 2), and cytokines in the microenvironment (signal 3). However, when pre-existing ETASTs, initially activated by tumor antigens, encounter the corresponding antigens in vitro or in the blood, they are reactivated by only signal 1.
- In this study, nanoparticles loaded with whole-cell tumor antigens are defined as tumor antigen-specific T cell activation nanoparticles (TATANs). In this research, the process of activating T cells in vitro using nanoparticles loaded with whole-cell tumor antigens is indirectly conducted by autologous antigen-presenting cells (APCs), simulating in vivo activation of pre-existing tumor antigen-specific T cells (TASTs) in peripheral tissues. T cells (ETASTs) that recognize tumor antigens are activated upon encountering the tumor antigen in vitro, allowing for the detection of activated ETASTs. Thus, the structural differences between ETASTs and other T cells are transformed into differences between activated and non-activated states, and the activation state can be differentiated by detecting activation biomarkers (such as IFN-γ and CD137).
- In esophageal cancer research, it has been found that nanoparticles loaded with whole-cell tumor antigens are more effective in activating ETASTs compared to nanoparticles loaded with multiple peptides or free tumor lysates. More importantly, nanoparticles loaded with a mixture of xenogeneic tumor tissues or lysates from multiple homogeneous cancer cell lines can achieve the same activation and detection effect as nanoparticles loaded with autologous tumor tissue lysates. By monitoring changes in peripheral blood ETASTs before and after immunotherapy in cancer patients, the feasibility of using these nanoparticles to predict immunotherapy efficacy based on activated ETAST detection has been proven. This method offers a promising and efficient predictive biomarker for immunotherapy, with high accuracy, specificity, accessibility, and minimal invasiveness.
- References [1] https://doi.org/10.1002/advs.202409913 [2] https://doi.org/10.1021/acs.analchem.4c04049
Arushi Jha
This study investigates biomarkers that predict how well immunotherapy will work in esophageal and lung cancer patients, aiming to personalize treatment and improve outcomes.
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