Lifting the innate immune barriers to antitumor immunity

Abstract

The immune system evolved for adequate surveillance and killing of pathogens while minimizing host damage, such as due to chronic or exaggerated inflammation and autoimmunity. This is achieved by negative regulators and checkpoints that limit the magnitude and time course of the immune response. Tumor cells often escape immune surveillance and killing. Therefore, disrupting the brakes built into the immune system should effectively boost the anticancer immune response. The success of anti-CTLA4, anti-PD-1 and anti-PD-L1 have firmly established this proof of concept. Since the response rate of anti-CTLA4, anti-PD-1 and anti-PD-L1 is still limited, there is an intense effort for the identification of new targets and development of approaches that can expand the benefits of immunotherapy to a larger patient pool. Additional T cell checkpoints are obvious targets; however, here we focus on the unusual suspects—cells that function to initiate and guide T cell activity. Innate immunity is both an obligate prerequisite for the initiation of adaptive immune responses and a requirement for the recruitment of activated T cells to the site of action. We discuss some of the molecules present in innate immune cells, including natural killer cells, dendritic cells, macrophages, myeloid-derived suppressor cells, endothelial cells and stromal cells, that can activate or enhance innate immune cell functions, and more importantly, the inhibitors or checkpoints present in these cells that restrain their functions. Boosting innate immunity, either by enhancing activator functions or, preferably, by blocking the inhibitors, may represent a new anticancer treatment modality or at least function as adjuvants to T cell checkpoint inhibitors.

A three-gene signature based on tumour microenvironment predicts overall survival of osteosarcoma in adolescents and young adults

“…Regrettably, the mechanism by which these three genes affect the prognosis of patients with OSs is still unclear, and it is worth exploring in the future. We speculate that COCH overexpression may induce the secretion of multiple cytokines and enhance the recruitment of immune cells, leading to the imbalance of the local inflammatory environment of TME and mediating the immune escape of tumor cells [ 59 – 61 ]. Similarly, MYOM2 overexpression may also mediate the malignant phenotype of tumor cells by affecting the inflammatory response of TME [ 49 – 51 ].…”

“…On the other hand, OSs cells could regulate the recruitment and differentiation of immune infiltrating cells (TIICs) to establish a local immune tolerance environment that was conducive to tumor growth, drug resistance and metastasis. OSs cells also could control the T-lymphocyte responses via the PD-1/PDL-1 system to affect the balance between M1 and M2 macrophage subtypes, then leading to immune tolerance [ 58 , 59 ]. A study used whole genome, T cell receptor sequencing and other methods to analyze the immune status of OSs, and confirmed that there were likely multiple immune-suppressive features in OSs, which might lead to poor response to immune checkpoint inhibitors and neoadjuvant chemotherapy [ 67 ].…”

Perspective on dietary isothiocyanates in the prevention, development and treatment of cancer

“…There is a growing understanding that CAFs play a key role in immunosurveillance in the tumor microenvironment. In parallel, and even earlier, innate immune responses elicited from the surrounding normal cells would cause release of inflammatory mediators necessary for the full-blown immune response [93] . However, in the resulting complex of immune cells both inhibitors and checkpoints are produced and can suppress innate immunity.…”

Shp1 in Solid Cancers and Their Therapy

“…The repertoire of Shp1 functions is continuously expanding to include the modulation of the tumor microenvironment, thus suggesting new potential therapeutic implications. In recent years cancer immunotherapy, which exploits T-cells to arm the immune system against tumoral cells, has shown promising results based on a multitude of targeting strategies such as immunomodulatory monoclonal antibodies, adoptive cell transfers, high-dose immunostimulatory cytokines, and others (93). Among these, encouraging results have been achieved through the targeting of inhibitory crucial molecules of the antitumor T-cell response such as programmed-cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (93).…”