What We're Reading
Cancer Immunol Res February 1 2021 9 (2) 127-127;
Combined BRAF, MEK, and CDK4/6 inhibition is being tested in clinical trials for treating melanoma. The authors show this combination depletes tumor-associated myeloid cells in the tumor immune microenvironment, which renders tumors unresponsive to immune checkpoint blockade.
Neutrophil-mediated ADCC is dependent on CD11b/CD18-integrin–mediated conjugate formation and is controlled by CD47–SIRPα signaling. By using LAD3-derived neutrophils, it is demonstrated that CD47–SIRPα signaling controls CD11b/CD18-integrin inside-out activation during conjugate formation in a kindlin3-dependent manner.
The B7 family member HHLA2 delivers costimulatory signals via TMIGD2. The data show that KIR3DL3 is an inhibitory receptor for HHLA2 and that HHLA2 is expressed in kidney cancer separately from PDL1; targeting this interaction could be immunotherapeutic.
Nutlin-3a, a small molecule antagonizing the inhibitory MDM2–p53 interaction, has a p53-dependent immunomodulatory effect on neuroblastoma. Nutlin-3a increases neuroblastoma's susceptibility to NK-cell killing, highlighting how this compound could be prospectively employed for an NK cell–based immunotherapy.
It is challenging to develop metabolism-targeted therapeutics because T cells and cancer cells have similar metabolic properties. The authors develop an in vitro pharmacologic screening platform and highlight ferroptosis as a metabolic vulnerability of CD8+ T cells.
Myeloid cell CXCR2 affects not only suppressive MDSCs but also B cells, especially the B1b subset. CXCL11-producing B cells are key and impact infiltration and activation of effector CD8+ T cells in the tumor microenvironment.
The influence of obesity on cancer immunotherapy is not clear. This study shows oxidized LDL promotes resistance to immunotherapy by suppressing T-cell function and driving tumor cytoprotection mediated by heme oxygenase-1 (HO-1), suggesting HO-1 is a promising therapeutic target.
Dietary fructose can be utilized by tumor cells and promotes cytoprotection by inducing HO-1 expression, thereby impacting TIL responses and immunotherapy outcomes. The data highlight a novel immune evasion mechanism and a potential therapeutic target.
Treatment of established tumors with a combination “pentatherapy” regimen leads to T-cell activation while decreasing Treg suppression. The data highlight how the combination of multimodal immunotherapy agents can engage, enhance, and enable adaptive antitumor responses.