As one of the commonest contributors to human death, cancer has always been a key research area for scientists from all over the world. In a recently published Perspective in Nature Reviews Clinical Oncology, researchers from the International Agency for Research on Cancer predict that, if without additional cancer control programs, 34 million new cancer cases will annually occur by 2070, double the number that occurred in 2020 (Isabelle et al., 2021). There is an urgent demand to find effective means of cancer prevention and treatment.
Traditional cancer treatments are mainly surgery, radiotherapy and chemotherapy. However, with the advancement of medical science, novel immunotherapies continue to emerge and to be incorporated into the existing strategies, providing new potential treatment options for cancer patients.
A Protease Enzyme Released by Human Neutrophils to Selectively Kill Cancer Cells
Prevailing treatments for cancer rely on surgery, radiation and chemotherapy, which are all seriously dissatisfactory due to their limited therapeutic potential. Specifically, surgery and radiation can be applied only in certain circumstances where tumor cells can be seen on imaging scans to avoid damaging to healthy tissues. Chemotherapy, as a current mainstay cancer treatment, has been extensively exploited in clinic thanks to its inherent simpleness and convenience. However, the problem consists in its low efficiency in drug delivery, nonspecific drug distribution and associated underlying side effects such as hair loss, weakness and immune-depression as the chemical agents could be toxic to normal cells as well as malignant tumors. Like every war happened in human history, a victory of a traditional treatment against malignant cells cost many lives of non-cancer ones as well.
A solution to “subdue the enemy without fighting” comes from scientists at the University of Chicago. They reported a few weeks ago in Cell that a protease enzyme called neutrophil elastase (ELANE) released by human neutrophils is capable of killing various cancer cell types while sparing heathy cells, which can be exploited as a broad therapy to treat diverse cancers with little risk of eliciting off-tumor toxicity (Cui et al., 2021). ELANE kills cancer cells by activating the programmed cell death. ELANE proteolytically liberates the CD95 death domain, which interacts with histone H1 isoforms to selectively kill cancer cells. This process also protects the immune system and enhances the immune response.
A Small Molecule-based Potent Cancer Chemo-immunotherapy
Tumor cells are able to go around immune attack by binding programmed death-ligand 1 (PD-L1) to programmed death protein1 (PD-1) on cytotoxic T cells and make them dysfunction. Therefore, immune response against tumor can be restored by antibodies that block the receptor-ligand interaction and normalize T cells. However, due to reasons like poor tumor penetration of large-size antibodies, such immune checkpoint blockade therapy is often ineffective in melanoma and solid tumors.
In a new publication in Nature Communications, researchers from Zhejiang University report a highly potent immunotherapeutic small molecule, 5-carboxy-8-hydroxyquinoline (IOX1), that combined with a cancer chemotherapeutic agent, doxorubicin, can reduce the growth of various murine tumor models and boost a long-term antitumor immunological memory (Liu et al., 2021). The findings presented in this article provide evidence of a potential high-efficiency antibody-free chemo-immunotherapy for cancer treatment.
A Biomarker Indicating the Efficacy of Immunotherapy for Pancreatic Cancer
Immunotherapies have cemented themselves as standard treatments for many cancers, but it is not effective in pancreatic cancer, which is known as “the cancer king”. The mechanism behind the disease and the target population remains unclear.
Previous studies have shown that the desmoplastic stroma in pancreatic cancer may be an important reason for the insensitivity of it to a variety of treatments, especially that of immunotherapy. Cancer-associated fibroblasts (CAF) are major components in the stroma of pancreatic cancer.
Recently, Wang et al. identified a novel CAF subtype with a highly activated metabolic state (meCAFs) in loose-type pancreatic ductal adenocarcinoma (PDAC) as a biomarker to predict the efficacy of immunotherapy for the disease (Wang et al., 2021). They illustrated the intertumoral heterogeneity of cellular components, immune activity, and metabolic status between dense- and loose-type PDACs. The results revealed meCAFs as a critical component for PDAC progression and the susceptibility to immunotherapy. The richness of meCAFs in PDAC patients was related to poor overall survival but predicted a better response to immunotherapy for patients.
A Therapeutic Vaccine to Treat Existing Tumors
Tumor lymphangiogenesis is associated with multiple immune regulatory processes leading to an immune-infiltrated tumor microenvironment and can be theoretically exploited to boost anti-tumor immunity. Nevertheless, previous reports have already shown that the direct stimulation of tumor-associated lymphangiogenesis could also promote cancer cell dissemination and metastasis, posing a new threat to patients’ health after the treatment (Farnsworth et al. 2018). Therefore, Sasso et al. sought to develop a therapeutic lymphangiogenic vaccine that harnesses lymphatics-induced immune responses and avoids direct involvement of lymphatic vessels within the tumor (Sasso et al. 2021).
To this end, they developed a cancer vaccine based on lymphangiogenesis-associated T cell immunity by using lethally irradiated tumor cells. They tested the vaccine in mice and found that the vaccine induced tumor growth inhibition in all recipient animals. Moreover, when tumor cells were reintroduced after 10 months, immune memory remained and prevented the growth of new tumors. Those results indicated that the vaccine could elict long-lasting anti-cancer protection as well as treat already existing tumors.
Cui, Chang, et al. "Neutrophil elastase selectively kills cancer cells and attenuates tumorigenesis." Cell 184.12 (2021): 3163-3177.
Farnsworth, Rae H., Marc G. Achen, and Steven A. Stacker. "The evolving role of lymphatics in cancer metastasis." Current opinion in immunology 53 (2018): 64-73.
Liu, Jing, et al. "Co-delivery of IOX1 and doxorubicin for antibody-independent cancer chemo-immunotherapy." Nature communications 12.1 (2021): 1-17.
Sasso, Maria Stella, et al. "Lymphangiogenesis-inducing vaccines elicit potent and long-lasting T cell immunity against melanomas." Science Advances 7.13 (2021): eabe4362.
Soerjomataram Isabelle, and Freddie Bray. "Planning for tomorrow: global cancer incidence and the role of prevention 2020–2070." Nature Reviews Clinical Oncology (2021): 1-10.
Wang, Yu, et al. "Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response." Cell discovery 7.1 (2021): 1-17.
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