Abstract
Adoptive cellular immunotherapy using chimeric antigen receptor (CAR)-modified T cells and Natural Killer (NK) cells are common immune cell sources administered to treat cancer patients. In detail, whereas CAR-T cells induce outstanding responses in a subset of hematological malignancies, responses are much more deficient in solid tumors. Moreover, NK cells have not shown remarkable results up to date. In general, immune cells present high plasticity to change their activity and phenotype depending on the stimuli they receive from molecules secreted in the tumor microenvironment (TME). Consequently, immune cells will also secrete molecules that will shape the activities of other neighboring immune and tumor cells. Specifically, NK cells can polarize to activities as diverse as angiogenic ones instead of their killer activity. In addition, tumor cell phagocytosis by macrophages, which is required to remove dying tumor cells after the attack of NK cells or CAR-T cells, can be avoided in the TME. In addition, chemotherapy or radiotherapy treatments can induce senescence in tumor cells modifying their secretome to a known as “senescence-associated secretory phenotype” (SASP) that will also impact the immune response. Whereas the SASP initially attracts immune cells to eliminate senescent tumor cells, at high numbers of senescent cells, the SASP becomes detrimental, impacting negatively in the immune response. Last, CAR-T cells are an attractive option to overcome these events. Here, we review how molecules secreted in the TME by either tumor cells or even by immune cells impact the anti-tumor activity of surrounding immune cells.
Highlights
Today, it is widely recognized that chronic inflammation is a driver of cancer [1], being estimated that 15-20% of cancers are inflammation-related [2]
A third transient population, known as decidual Natural Killer (NK) cells, present at the fetal-maternal interface during the first months of pregnancy, representing 70% of immune cells in the decidua. dNK cells are known as uterine NK cells, as classically, uNK cells were detected by Dolichos biflorus agglutinin (DBA) lectin staining, where DBA+ cells were defined as dNK cells
We described that NK cells release histones that bind to and degrade the syndecans on the glycocalyx of multiple myeloma cells [145], suggesting that by doing this, NK cells might promote the phagocytosis of tumor cells by macrophages, an event observed during fungal infection [146]
Summary
It is widely recognized that chronic inflammation is a driver of cancer [1], being estimated that 15-20% of cancers are inflammation-related [2] This association has been observed in different contexts, such as persistent Helicobacter pylori infection or autoimmune diseases like inflammatory bowel disease that increase the risk of developing gastric cancer [3] or colorectal cancer [4], respectively. IL1b inhibition reduced CRP and IL6 levels and the incidence of developing lung cancer in patients with atherosclerosis who had a myocardial infarction [7] Both immune and tumor cells promote this proinflammatory microenvironment. The different subsets of immune cells will release immunosuppressive and inflammatory factors that will shape the tumor microenvironment (TME), promoting or inhibiting cancer progression [13]. We will focus on the impact on T cells, CAR-T cells, and NK cells, which are currently used in adoptive cellular immunotherapy [14,15,16,17, 31], and macrophages
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