For many years, researchers have been trying to develop the most effective ways to fight lung cancer, which is the cause of the largest number of cancer-related deaths among men and women worldwide. The most advanced treatments for nearly all non-small-cell lung cancer (NSCLC) types include immunotherapy with immune checkpoint inhibitors (ICIs), mainly anti-programmed death 1/anti-programmed death ligand 1 monoclonal antibodies (anti-PD-1/PD-L1 mAbs) in monotherapy or in combination with other strategies. Despite significant advances, long survival is not achievable in most cases, so new solutions are constantly being sought. One of the questions raised by oncologists is the efficacy of ICIs in patients with molecular driver alterations, especially when the possibilities of using molecularly targeted therapies are exhausted (e.g., due to resistance to tyrosine kinase inhibitors). There are studies investigating this problem, but it is still poorly described. Among probable immunotherapy’ failures reasons, low immunogenicity of tumors with one driver mutation is listed. Nevertheless, in some cases, the therapy is efficient, and more research is required to establish the management of NSCLC patients with oncogenic driver abnormalities. The aim of this article is to review current discoveries in this matter.

Currently, one of the leading treatments for non-small-cell lung cancer is immunotherapy involving immune checkpoint inhibitors. These monoclonal antibodies restore the anti-tumour immune response altered by negative immune checkpoint interactions. The most commonly used immunotherapeutics in monotherapy are anti-PD-1 and anti-PD-L1 antibodies. The effectiveness of both groups of antibodies has been proven in many clinical trials, which have translated into positive immunotherapeutic registrations for cancer patients worldwide. These antibodies are generally well tolerated, and certain patients achieve durable responses. However, given the resistance of some patients to this form of therapy, along with its other drawbacks, such as adverse events, alternatives are constantly being sought. Specifically, new drugs targeting already known molecules are being tested, and new potential targets are being explored. The aim of this paper is to provide an overview of the latest developments in this area.

The efficiency of immunotherapy using monoclonal antibodies that inhibit immune checkpoints has been proven in many clinical studies and well documented by numerous registration approaches. To date, PD-L1 expression on tumor and immune cells, tumor mutation burden (TMB), and microsatellite instability (MSI) are the only validated predictive factors used for the qualification of cancer patients for immunotherapy. However, they are not the ideal predictive factors. No response to immunotherapy could be observed in patients with high PD-L1 expression, TMB, or MSI. On the other hand, the effectiveness of this treatment method also may occur in patients without PD-L1 expression or with low TMB and with microsatellite stability. When considering the best predictive factor, we should remember that the effectiveness of immunotherapy relies on an overly complex process depending on many factors. To specifically stimulate lymphocytes, not only should their activity in the tumor microenvironment be unlocked, but above all, they should recognize tumor antigens. The proper functioning of the anticancer immune system requires the proper interaction of many elements of the specific and non-specific responses. For these reasons, a multi-parameter analysis of the immune system at its different activity levels is considered a very future-oriented predictive marker. Such complex immunological analysis is performed using modern molecular biology techniques. Based on the gene expression studies, we can determine the content of individual immune cells within the tumor, its stroma, and beyond. This includes all cell types from active memory cytotoxic T cells, M1 macrophages, to exhausted T cells, regulatory T cells, and M2 macrophages. In this article, we summarize the possibilities of using an immune system analysis to predict immunotherapy efficacy in cancer patients. Moreover, we present the advantages and disadvantages of immunoprofiling as well as a proposed future direction for this new method of immune system analysis in cancer patients who receive immunotherapy.

Introduction The expression of PD-L1 (programed cell death ligand 1) protein on neoplastic cells is a factor qualifying cancer patients for immunotherapy. However, the status of PD-L1 mRNA expression in plasma or serum has not been well studied in cancer patients. TP-53 (Tumor Protein p53) as tumor suppressor affects the expression of many genes, including microRNAs that regulate PD-L1 expression. Purpose of our study was to evaluate usefulness of analysis of PD-L1 mRNA, microRNAs and TP-53 mRNA expression in liquid biopsy in non-invasive diagnosis of non-small cell lung cancer patients (NSCLC).Material and methods We examined the expression the expression of TP-53 and PD-L1 mRNA as well as seven microRNAs (miR-17, miR-93, miR-142, miR-519, miR-526, miR-34a-5p and miR-34a-3p) in plasma obtained from 80 NSCLC patients and 39 healthy volunteers. We used quantitative PCR preceded by reverse transcription method.Results We observed PD-L1 mRNA expression only in 6 (7.5%) NSCLC patients. We showed that expression of TP-53 mRNA and each tested microRNAs were significantly higher in healthy person than in NSCLC patients. Based on the Receiver Operating Characteristic (ROC) analysis, we found that TP-53 mRNA and each of examined microRNAs expression were good diagnostic markers for non-invasive diagnosis of NSCLC. We found a significant, negative correlation between TP-53 mRNA and miR-17 (R=-045, p=0.0005) as well as miR-34a-5p (R=-0.32, p=0.04) expression in patients with advanced NSCLC.Conclusion The decreased expression of TP-53 mRNA may influence the disruption of microRNAs which could be involved in the regulation of PD-L1 expression in NSCLC patients

Introduction The expression of PD-L1 (programed cell death ligand 1) protein on neoplastic cells is a factor qualifying cancer patients for immunotherapy. However, the status of PD-L1 mRNA expression in plasma or serum has not been well studied in cancer patients. TP-53 (Tumor Protein p53) as tumor suppressor affects the expression of many genes, including microRNAs that regulate PD-L1 expression. The purpose of our study was to evaluate usefulness of analysis of PD-L1 mRNA, microRNAs and TP-53 mRNA expression in liquid biopsy in non-invasive diagnosis of non-small cell lung cancer patients (NSCLC). Material and methods We examined the expression the expression of TP-53 and PD-L1 mRNA as well as seven microRNAs (miR-17, miR-93, miR-142, miR-519, miR-526, miR-34a-5p and miR-34a-3p) in plasma obtained from 80 NSCLC patients and 39 healthy volunteers. We used quantitative PCR preceded by reverse transcription method. Results We observed PD-L1 mRNA expression only in 6 (7.5%) NSCLC patients. We showed that expression of TP-53 mRNA and each tested microRNA were significantly higher in healthy individuals than in NSCLC patients. Based on the Receiver Operating Characteristic (ROC) analysis, we found that TP-53 mRNA and each of the examined microRNAs expression were good diagnostic markers for non-invasive diagnosis of NSCLC. We found a significant, negative correlation between TP-53 mRNA and miR-17 (R=-045, p = 0.0005) as well as miR-34a-5p (R=-0.32, p = 0.04) expression in patients with advanced NSCLC. Conclusion The decreased expression of TP-53 mRNA may influence the disruption of microRNAs which could be involved in the regulation of PD-L1 expression in NSCLC patients