Immune microenvironments in solid tumors: new targets for therapy

Abstract

Leukocytes and their soluble mediators play important regulatory roles in all aspects of solid tumor development. While immunotherapeutic strategies have conceptually held clinical promise, with the exception of a small percentage of patients, they have failed to demonstrate effective, consistent, and durable anti-cancer responses. Several subtypes of leukocytes that commonly infiltrate solid tumors harbor immunosuppressive activity and undoubtedly restrict the effectiveness of these strategies. Several of these same immune cells also foster tumor development by expression of potent protumor mediators. Given recent evidence revealing that immune-based mechanisms regulate the response to conventional cytotoxic therapy, it seems reasonable to speculate that tumor progression could be effectively diminished by combining cytotoxic strategies with therapies that blunt protumor immunebased effectors and/or neutralize those that instead impede development of desired anti-tumor immunity, thus providing synergistic effects between traditional cytotoxic and immune-modulatory approaches.

Immunomodulatory properties of silver nanoparticles contribute to anticancer strategy for murine fibrosarcoma

“…Moreover, in the tumor immune microenvironment, there are multiple immune checkpoints that control the tumor surveillance inside organisms. 52 The cytokine levels in the different experimental groups showed a tumor immunomodulation by the AgNP-MSA, which ultimately affects the immune checkpoints.…”

Tumor-Associated Hyaluronan Limits Efficacy of Monoclonal Antibody Therapy

“…Targeted mAb therapy for human solid tumors relies on binding of the mAb to tumor cell surface target receptors followed by intracellular signaling attenuation to sensitize tumor cells, direct tumor cell killing by FcgIIIA (CD16)-expressing immune cells, and mAb-mediated host immune response activation. Success of mAb therapies in the clinic is limited by several underlying mechanisms including underappreciated TME-mediated host immune response suppression, such as reduced malignant cell killing by CD8 þ CTLs and/or NK cells, and properties of some immune cells harboring protumor activities (25). In addition, tumor cells have been shown to use multiple immunosuppressive mechanisms to avoid host immune attack, including tumor-induced impairment of antigen presentation (41,42), secretion of immunosuppressive and growth factors (e.g., TGFb and IL10) in the TME (43,44), amplification of receptor tyrosine kinases (45), upregulation/expression of negative costimulatory signaling molecules (CTLA-4 binding CD80 and/or CD86, PD-L1 and/or PD-L2) by tumor cells (46,47), inhibition of dendritic cell differentiation and maturation (44,46), and increased infiltration of regulatory T-cells (48,49).…”

“…Multiple mechanisms of resistance to these mAbs have been described previously (17,(19)(20)(21)(22)(23)(24). Recently, the role of the tumor ECM has been recognized as a potential contributor to therapeutic resistance (7,25,26).…”

Immunological Mechanisms of Low and Ultra-Low Dose Cancer Chemotherapy

“…It is clear that there is significant interaction between chemotherapeutic drugs, dying tumor cells, and local immune cells that have various effects on tumor immunogenicity, and many of these effects have been previously described using traditional, MTD drug regimen strategies [12]. These include both immunogenic effects, such as paclitaxel and doxorubicin enhancing antigen-specific Th1 immune responses and tumorigenic effects such as prolonged T cell and B cell depletion [13,14].…”