by Rituparna Mishra
Cancer is a disease where a malignant tumour is formed due to cells dividing uncontrollably and it is capable of affecting other body parts excluding its origin. Amidst the COVID-19 situation, there are millions battling cancer, and some battling both diseases. There are many treatments offered to treat cancer, however primarily cancer is usually treated through surgery. Different therapies such as radiotherapy, chemotherapy and immunotherapy are also commonly used, with immunotherapy being one of the most effective treatment methods as it can be used to treat almost any type of cancer.
Recently, researchers have studied further about immunotherapy, and have found different approaches to increase the effectiveness of this therapy. One approach is the inhibition of LRG1 (Leucine Rich Alpha 2 Glycoprotein), a protein coding gene, which has shown great responses in boosting immune therapies and better targeting of tumour vasculatures. A tumour vasculature has an imbalance in the pro-angiogenic and anti-angiogenic factors causing aberrant structural dynamics, which include vessels which are undeveloped and coiled up. The widely accepted idea is that antiangiogenic therapies can not only help destroy tumour vasculature, but also ‘normalise’ it’s abnormal structure. This is said to help in improving the treatments of various cancers, however, antiangiogenic therapies have failed to improve the survival rate of cancer patients, however, it helps to improve vascular functionality which in turn could aid in both, T cell trafficking and increasing tumour response to immunotherapy. Although there have been successful clinical trials, broad clinical implementation is still limited due to insufficient understanding of the mechanisms involved in tumour-associated vessel dysfunction and identification of the most advantageous drug regimens that can maintain normal vasculature conditions in various body tissues.
LRG1 binds to endoglin (a TGF - β accessory receptor), and in the presence of TGF - β1, it promotes pro-angiogenic signalling pathways. Further studies have shown that LRG1 antibody blockage results in impaired angiogenesis, and therefore discovered that through the modulation of TGF - β, angiogenesis’ effect can be mediated. This in fact, has led to problems such as dysfunctional blood vessel growth, and recently LRG1 was also identified to have been an inflammatory factor of the premetastatic lung microvasculature. Therefore, greater levels of LRG1 expression by either endothelial or cancel cells have intensified the serum levels of LRG1, disrupted the working of blood vessels and has created a non-restrictive opportunity for cancer cell seeding and outgrowth. O’connor, a medical group for internal medicine and pediatrics has studied on LRG1 and tested the corresponding hypothesis of its inhibition resulting in a vascular normalisation that combines with improved immune responses. The results showed that LRG1 is induced in the carcinomas of the lung, breast and leads to higher serum levels of patients with pancreas carcinomas. Interestingly, in preclinical mouse models, it was seen that the genetic and antibody based inhibition of LRG1 indicated a more functional tumor vasculature, with the primary results showing increased vascular patency, blood vessel perfusion and mural cell coverage. However, as inhibition of LRG1 by itself was sufficient enough to block tumor vasculatures, the question of whether the normalisation of tumor vasculature by LRG1 inhibition could synergise with anticancer therapies was raised.
To answer this doubt, O’connor explored the combination therapy by grouping up the LRG1-targeting antibody with ICB in a mouse model, the adoptive T cell theory and cisplatin. In all cases, the combined therapy showed consistent results with increased efficiency and improved tumor control, and supported the hypothesis of targeting vascular function to be a critical factor for the effectiveness of combined treatments. However, there may be problems relating to the mechanism of normalisation, as it may vary depending on the target site or therapeutic agent, like, for instance, the usage of ICB(a type of immunotherapy which uses immune checkpoint blockade inhibitors to identify cancer) and VEGF(Vascular Endothelial Growth Factor which is a key mediator of angiogenesis in cancer) pathway inhibitors may cause T cell infiltration in HEV vessels. However, so far, no such evidence has been found to back up this possibility, although in future this may be raised in opposition of LRG1’s role in vascular normalising. Nevertheless, O’connor’s endless experiments, and preclinical trials have proven that the inhibition of LRG1 aids in improved immune therapies, and that combined therapies will definitely open more opportunities for more efficient cancer treatments.
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