The immune system and malignant neoplasms: fundamental and translational aspects

1 - Oncology Research Institute of the Federal State Budgetary Scientific Institution "TNIMTS RAS", 2 - National Research Tomsk State University, 3 - Siberian State Medical University, Tomsk, Russia

The immune system is responsible for control of the antigenic continuity, ensuring the friend-or-foe identification and the formation of appropriate responses by the organism, aimed either at destruction (in case of infection with infectious pathogens and transplantation of an alien graft), or protection of the "foe" to be incorporated by the host organism (under physiological pregnancy, or in case of pathology under malignant growth) [1].

The immune system closely interacts with the DNA Damage Response (DDR) system, which, together with other signaling pathways, ensures the repair of damaged genetic material. In the presence of a defect in the repair system, for example, with congenital mutations in the BRCA 1/2 repair genes, genomic instability appears as a basis for the development of cancer. This determines clonal evolution through an accumulation of driver aberrations (CNA, chromosomal rearrangements, mutations), malignancy, and progression of a malignant process, primarily associated with distant metastases [2].

Genetic disorders lead to development of an immune response to new antigenic determinants arising from DNA damage as a result of some congenital or somatic mutations. The DDR-deficient cancer cells are recognized by the immune system, and it should be noted that chemotherapy and radiotherapy of patients also have a DNA-damaging effect. Innate immunity is involved through GMP-AMP synthase signaling, a stimulator of type 1 IFN gene (cGAS-STING signaling), with activation of an adaptive response (effectors of T-lymphocytes) [3].

The expression of the IFN genes can act as a predictor of the effects of immunotherapy.

The phenomenon of tumor prevention by the immune system exists, but it is difficult to explore, since it is impossible to trace under natural conditions, because the tumor does not develop in this case.

The immune system plays an important role (in cooperation with other components of the microenvironment) in tumor progression, stimulating the prometastatic properties of the tumor cells, helping increase their mobility, entry into the bloodstream, and transition to metastasis sites. We have obtained original data on the phenotype and expression profiles of the tumor cells, which should have the attributes of “seed cells”, that is, capable of giving rise to a tumor focus. But however this requires the presence of some prepared premetastatic niches to have suitable conditions for activating the proliferation and growth of the cells entering there, or some conditions 16

for awakening dormant cells and forming a secondary tumor [4]. The cells of the immune system constitute the inflammatory infiltrate of the microenvironment and are the main effectors against the tumor cell (T lymphocytes, macrophages associated with the tumor).

All existing present-day cancer therapies involve the immune system as an additional effector or regulatory influence, acting either in favor of the tumor or initiating an adaptive immune response directed against the tumor. Modern immunotherapy approaches (immune response checkpoint inhibitors proposed by James Allison and Tasuku Honjo, the 2018 Nobel Laureates in Physiology or Medicine) also apparently recruit the immune system to produce an antitumor response. However, the number of patients who received a therapeutic effect upon immunotherapy is far from that expected (20-30%), and, most importantly, the evidence data have recently been obtained on the phenomenon of the development of a fatal progression at such immunotherapy, leading to a sudden death of patients. In this regard, scientists face a vital task to determine both the indications for immunotherapy and find markers for predicting its effectiveness, and, importantly, some markers which may identify the risk of hyperprogression.

Improved effectiveness of the use of checkpoint inhibitors can be associated with their possible combination with targeted drugs aimed at specific molecular disorders, epigenetic regulators, and their target in cancer patients is the tumor microenvironment, so its modification should create conditions for an antitumor response.

Thus, the immune system can control the behavior of the tumor, even under various therapeutic effects, and allows controlling the effect of immunotherapy. The translation of immunotherapy approaches into clinical practice has the prospect for increasing the effectiveness of treatment based on the search for adequate markers of prognosis and prediction as well as targets for therapy.