Abstract
Pulmonary carcinomas have developed mechanisms by which they escape the attack of immune cells. Immune checkpoint molecules programmed death 1 - programmed death ligand 1 (PD1-PDL1) and the cytotoxic T-lymphocyte antigen 4 system have gained attention. The expression of PDL1 by tumor cells causes immune tolerance, and further influences the microenvironment via orchestration by cytokines. Therapy with PDL1 antibodies could restore the cytotoxicity of T-lymphocytes towards tumor cells. Many patients will respond to this treatment. However, resistance mechanisms will counteract this therapy. New investigations have identified additional immune checkpoint inhibitors such as lymphocyte activation gene 3 and T cell immunoglobulin and mucin-domain containing-3. Tumor cells also induce tolerance by manipulating cells of the innate immune system. Macrophages are polarized to tumor-friendly M2, neutrophils into N2 types, and dendritic cells and myeloid suppressor cells are switched to assist tumor cells. Regulatory T cells enter the tumor microenvironment and signal tolerance to cytotoxic cells, inhibiting the influx of NK cells. Soluble mediators either released by tumor cells or cells of the tumor stroma induce immune tolerance, examples including tryptophan and indolamine dioxygenases, arginine and adenosine. Treatment options to counteract these molecules are currently being tested. The tumor stroma has been classified as immune-inflamed, immune-excluded, and immune-desert types. The latter might be switched to an inflamed type by induction of tertiary lymph follicles. Dendritic cells and macrophages normally phagocytose tumor antigens, but inhibitors of phagocytosis can block this. Interference with these molecules is another option for re-establishing the cytotoxic action of the immune system against tumor cells. In this review we will discuss these aspects with a special emphasis on non-small cell lung cancer.
Highlights
Immunotherapy was first applied to melanomas, which is one of the malignancies with the highest mutational burden
Shortly after it was reported that non-small cell carcinoma (NSCLC) can be targeted by antibodies for immune checkpoint inhibitors
Programmed cell death 1 (PD1) and its ligand PDL1 was found on tumor cells as well as on lymphocytes inducing immune tolerance[2]
Summary
Immunotherapy was first applied to melanomas, which is one of the malignancies with the highest mutational burden. Shortly after it was reported that non-small cell carcinoma (NSCLC) can be targeted by antibodies for immune checkpoint inhibitors. Programmed cell death 1 (PD1) and its ligand PDL1 was found on tumor cells as well as on lymphocytes inducing immune tolerance[2]. Based on these findings, antibodies for PDL1 and PD1 were tested for their ability to interfere with this mechanism of immune tolerance against tumor antigens. Several pharmaceutical companies have developed checkpoint inhibitors (humanized monoclonal antibodies) for the treatment of NSCLC patients and several phase II and III studies have been performed. Whereas some drugs are selectively approved for squamous cell carcinomas (SCC), others may be used in all NSCLC[9,11,12,13,14]
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