Immune cell infiltrate profiling with mass cytometry
Multiscale immune profiling strategies based on mass cytometry were developed to examine the immune microenvironment in clear cell renal cell carcinoma (Chevrier et al.) and early lung adenocarcinomas (Lavin et al.). Both studies found multiple diverse subtypes of lymphoid and myeloid lineage cells and noted combinations of cells that correlate with progression-free survival or impaired antitumor immunity.
Chromatin states define tumour-specific T cell dysfunction and reprogramming
The epigenetic state of tumor-specific CD8+ T cells evolves during tumor development, with two clear chromatin states emerging, based on accessibility of particular chromatin regions. After an initial dynamic and reversible period of change, a non-plastic state recognizable by CD38 and CD101 expression was established in which T cells could not be reprogrammed back to a functional state.
Interferon-γ drives Treg fragility to promote anti-tumor immunity
Neuropilin-expressing Tregs congregate in certain tumors and are correlated with poor prognoses. Neuropilin strengthened Treg resistance to destabilization by IFNγ produced in tumor sites, which disrupted Treg function. Effective PD-1 blockade required such IFNγ signaling in Tregs. Targeting neuropilin may promote antitumor immunity while still allowing peripheral Tregs, which express much less neuropilin, to maintain tolerance.
PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity
Signaling through PD-1 inhibits T-cell activation. PD-1 was found on mouse and human tumor-associated macrophages, and increased as disease progressed. PD-1 stimulation inhibited phagocytic capacity, and blocking PD-1/PD-1 ligand interactions increased phagocytosis and reduced tumor burdens. Macrophage modulation by PD-1 may explain why cancers with T cells expressing little PD-1 may still respond to anti-PD-1/PD-L1 blockade.
Fc-optimized anti-CD25 depletes tumor-infiltrating regulatory T cells and synergizes with PD-1 blockade to eradicate established tumors
Antibodies to CD25 have limited efficacy as antitumor agents. Their propensity to deplete CD25-rich Tregs in the periphery, but not in tumors, was found to be due to increased inhibitory Fc receptors on intratumoral myeloid cells, preventing FcR-induced killing of Tregs. Optimized CD25 antibodies with enhanced binding to activating FcRs can be combined with checkpoint blockade to eradicate established tumors.
Structural basis for cancer immunotherapy by the first-in-class checkpoint inhibitor ipilimumab
The CTLA-4–specific mAb ipilimumab successfully impedes signals through CTLA-4 that inhibit T-cell activation. Ipilimumab was crystallized together with CTLA-4, and the structure revealed that ipilimumab competes with the B7 family CTLA-4 ligands by binding overlapping CTLA-4 surfaces. The structure also provided insight into ipilimumab's selectivity for CTLA-4 over the homologous, yet stimulatory, CD28 protein.
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