Tumor Secretome to Adoptive Cellular Immunotherapy: Reduce Me Before I Make You My Partner

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.

Development of a prognostic pyroptosis-related gene signature for head and neck squamous cell carcinoma patient

“…The results of these analyses suggest that this prognostic gene signature may have important implications for immunotherapy treatment planning. NK cell infiltration was related to the activation of pyroptosis [ 45 ] and alternatively differentiated macrophage (M2 macrophage) infiltration was associated with the decrease of inflammation and pyroptosis [ 46 ]. Interestingly, In the present study, we noted that NK cell infiltration was increased and macrophage infiltration was decreased in high-risk patients from the GSE65858 cohort, these results are also in line with the previous studies [ 28 , 29 ], indicating the distinct role of macrophages and NK cells in cancer development, and suggesting the potential role of immune cell-mediated activation of pyroptosis in affecting HNSCC patients outcome.…”

Pancreatic Cancer and Cellular Senescence: Tumor Microenvironment under the Spotlight

“…IL-1β, for instance, may modulate NK activity with opposite effects depending on the producing cell type. It has been shown that IL-1β secreted by macrophages increases NK cytotoxicity, while IL-1β produced by tumor cells impairs NK cell development and functions, recruiting MDSCs [ 184 , 185 ]. IL-6 and IL-8, other major components of the SASP, have been found to inhibit the cytotoxic activity of NK cells in different tumors through the down-regulation of perforin and Granzyme B [ 186 ].…”

A Novel Secreted Protein-Related Gene Signature Predicts Overall Survival and Is Associated With Tumor Immunity in Patients With Lung Adenocarcinoma

“…During the development of malignant tumors, tumor cells secrete a variety of proteins, such as cytokines and proteolytic enzymes. The secreted proteins display an altered composition compared to the normal tissue, and their expression levels may change during different tumor stages (63). Consequently, secreted proteins have become the main source of potential tumor markers (64,65).…”