Butyrophilin 2A1 is essential for phosphoantigen reactivity by γδ T cells
γδ T cells are essential for immunity. Human Vγ9Vδ2 T cells recognize phosphoantigens (pAgs) from microbes and tumors in an MHC-unrestricted manner. Activation induces inflammatory cytokine release and cytolytic activity. Utilizing genomic screening and binding analysis, the authors identify the butyrophilin 2A1 surface protein, in conjunction with its partner, BTN3A1, as essential for Vγ9Vδ2 T-cell recognition of pAgs by binding to the extracellular side of the Vγ9 subunit of the γδ TCR. This activates the γδ T cells to kill tumors and other cells expressing pAgs.
Single-cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species
The myeloid composition of the tumor microenvironment (TME) of non–small cell lung cancer (NSCLC) remains unclear. Single-cell transcriptional profiling of tumor-infiltrating myeloid cells (TIMs) from patients and mice with NSCLC reveals 25 distinct myeloid subsets and activation states. Most major myeloid lineages are common between species, and TIM populations from different patients also show coherence. Infiltrating myeloid subsets, however, only partially overlap with peripheral myeloid populations. Thus, TIM subpopulations are validated by cross-species detection and interpatient similarities, but blood samples cannot be used for insight into a patient's TME.
ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity
Many human pancreatic ductal adenocarcinomas (PDACs) contain IL33 receptor–bearing group 2 innate lymphoid cells (ILC2s), which are also enriched in the “hot” tumors of long-term survivors. In orthotopic mouse models of PDAC, IL33 can activate ILC2s to induce tumor regression, but not in pancreatic tumors implanted under the skin. The antitumor effect is improved by blockade of PD-1, which is the only coinhibitory molecule identified on ILC2s. Activation of these cells broadens the strategies available to enhance antitumor immunity, but tissue-specific effects require additional study.
Peripheral T cell expansion predicts tumour infiltration and clinical response
Is the success of immune checkpoint blockade due to reactivation or replenishment of T-cell clones? A comparison of single-cell RNA from tumor-infiltrating T cells (TILs), T cells from adjacent normal tissue, and those from blood reveals that expanded clonotypes in the tumor are also found in the other sites, pointing to expansion of new peripheral clones to replace exhausted TILs. Patients with this pattern respond better to anti–PD-L1. Peripheral blood clonotypes are thus representative and could be exploited for clinical assessment.
CDK7 inhibition potentiates genome instability triggering anti-tumor immunity in small cell lung cancer
Small cell lung cancer (SCLC) does not respond well to chemotherapy or checkpoint blockade, with recurrences resulting in 7% survival 5 years after diagnosis. CDK7 regulates the cell cycle, and a new inhibitor, YKL-5-124, can not only disrupt the cell cycle, but when incubated with SCLC cells also impairs replication and causes DNA damage, micronuclei formation, and genomic instability. In vivo YKL-5-124 induces T-cell inflammation, delays and reduces tumor growth, and prolongs survival. Combining CDK7 inhibition with anti–PD-1 further reduces tumor size, increases survival, and supports robust immune responses.
CRISPR-engineered T cells in patients with refractory cancer
To increase the efficacy and safety of engineered T cells, CRISPR/Cas9 is used to delete PD-1 and endogenous TCRs before receiving a new antitumor TCR (recognizing NY-ESO-1). In three patients, these injected T cells travel to the tumor and persist for more than 9 months, with little toxicity. Not all of the tumor is eradicated, but cells expressing the target protein are reduced, demonstrating on-target action. CRISPR technology provides a means to quickly engineer safer and more persistent antitumor T cells.
