Immune checkpoint blockade (ICB) therapy has brought unprecedented clinical benefits to cancer patients. Nevertheless, responses are far from universal, and many patients develop primary or acquired resistance to ICB, such as antibodies to immune checkpoint receptor CTLA-4, PD-1, and its ligand--PD-L1 that triggers PD-1 immune inhibitory signalling on T cells. There is an urgent need to uncover PD-L1/PD-1(PD)-independent, immune checkpoints in the tumour microenvironment (TME), as these molecules could provide targets for next-generation immunotherapies.
Given the increasing need to identify therapies beyond the PD pathways, it is critical to clearly understand the immune suppressive mechanisms within the TME to maximize therapeutic efficacy while limiting potential systemic immune toxicity. At the molecular level, these regulatory networks often form receptor/ligand interaction pairs at cell/cell interfaces. Immune evasion mechanisms in the TME of advanced human cancers are highly heterogeneous. Ample evidence supports that, in addition to the upregulation of PD-L1, many other molecular or cellular pathways/mechanisms also contribute to dysfunctional tumour immunity in the TME. These mechanisms include, but are not limited to, a lack of sufficient immune cell infiltration, accumulation of regulatory T cells, the presence of tumour-associated macrophages and myeloid-cell derived suppressive cells, as well as upregulation of suppressive molecules, cytokines, and metabolites, as well as molecules modulating tumour vascular biology for T cell penetration. Many of these mechanisms, however, may not be selective for the TME and, therefore, manipulation of these pathways could lead to either systemic activation of the immune system with a high risk of autoimmune toxicities or elicit little to no clinical efficacy. These results call for careful re-evaluation of their biology, cancer relevance and functionality in the regulation of tumour immunity. The current success of anti-PD therapy also highlights the importance of identifying and targeting tumour-related additional immune checkpoints that restore defective immune responses in the TME for the development of next-generation cancer immunotherapies.
This Research Topic will give a comprehensive overview about the novel immune checkpoints that critically affects tumour immunity, with particular emphasis on the molecular mechanisms in the tumour microenvironment and therapeutic applications in treating cancers. We welcome the submission of Original Research, Reviews, Mini-reviews and Perspective articles.
The themes addressed by this Research Topic will include, but are not limited to, the following:
• Key immune suppressive mechanisms of established immune checkpoint receptors/ligands beyond CTLA-4/PD-1, such as LAG-3, TIGIT, PVIRG, TIM3, HHLA2, CD47.
• Emerging T cell or NK checkpoint receptors or ligands in the control of tumour immunity
• Myeloid checkpoints that critically affect phagocytosis and T cell immunity in the TME
• Immune suppressive cytokines or metabolites as important mechanisms of tumour immune evasion
• Key regulators of tumour vasculature that affect immune penetration
Immune checkpoint blockade (ICB) therapy has brought unprecedented clinical benefits to cancer patients. Nevertheless, responses are far from universal, and many patients develop primary or acquired resistance to ICB, such as antibodies to immune checkpoint receptor CTLA-4, PD-1, and its ligand--PD-L1 that triggers PD-1 immune inhibitory signalling on T cells. There is an urgent need to uncover PD-L1/PD-1(PD)-independent, immune checkpoints in the tumour microenvironment (TME), as these molecules could provide targets for next-generation immunotherapies.
Given the increasing need to identify therapies beyond the PD pathways, it is critical to clearly understand the immune suppressive mechanisms within the TME to maximize therapeutic efficacy while limiting potential systemic immune toxicity. At the molecular level, these regulatory networks often form receptor/ligand interaction pairs at cell/cell interfaces. Immune evasion mechanisms in the TME of advanced human cancers are highly heterogeneous. Ample evidence supports that, in addition to the upregulation of PD-L1, many other molecular or cellular pathways/mechanisms also contribute to dysfunctional tumour immunity in the TME. These mechanisms include, but are not limited to, a lack of sufficient immune cell infiltration, accumulation of regulatory T cells, the presence of tumour-associated macrophages and myeloid-cell derived suppressive cells, as well as upregulation of suppressive molecules, cytokines, and metabolites, as well as molecules modulating tumour vascular biology for T cell penetration. Many of these mechanisms, however, may not be selective for the TME and, therefore, manipulation of these pathways could lead to either systemic activation of the immune system with a high risk of autoimmune toxicities or elicit little to no clinical efficacy. These results call for careful re-evaluation of their biology, cancer relevance and functionality in the regulation of tumour immunity. The current success of anti-PD therapy also highlights the importance of identifying and targeting tumour-related additional immune checkpoints that restore defective immune responses in the TME for the development of next-generation cancer immunotherapies.
This Research Topic will give a comprehensive overview about the novel immune checkpoints that critically affects tumour immunity, with particular emphasis on the molecular mechanisms in the tumour microenvironment and therapeutic applications in treating cancers. We welcome the submission of Original Research, Reviews, Mini-reviews and Perspective articles.
The themes addressed by this Research Topic will include, but are not limited to, the following:
• Key immune suppressive mechanisms of established immune checkpoint receptors/ligands beyond CTLA-4/PD-1, such as LAG-3, TIGIT, PVIRG, TIM3, HHLA2, CD47.
• Emerging T cell or NK checkpoint receptors or ligands in the control of tumour immunity
• Myeloid checkpoints that critically affect phagocytosis and T cell immunity in the TME
• Immune suppressive cytokines or metabolites as important mechanisms of tumour immune evasion
• Key regulators of tumour vasculature that affect immune penetration