Volume 3 Issue 6, June 2022

Tumor mutational burden (TMB) has received significant attention within ongoing pursuits of biomarkers of response to immune checkpoint inhibitors, and notably received FDA approval as a companion diagnostic biomarker for pembrolizumab. Here, four experts discuss the utility, challenges, and open questions surrounding TMB in the context of cancer immunotherapy.

The phenotypes of γδ T cells infiltrating human tumors and their role in anti-tumor immunity remain poorly understood. A new study demonstrates that Vδ1 lymphocytes with cytolytic potential and features of tissue-resident-memory differentiation are predictive of survival in patients with non–small-cell lung cancer.

Therapy resistance limits the clinical success of tyrosine kinase inhibitors (TKIs) in ALK-positive non-small cell lung cancer. A study now proposes a framework to identify compound resistance mutations to the lorlatinib TKI and provides structure-based drug design approaches to overcome resistance mediated by ALK(G1202R) or ALK(I1171N/S/T).

Prognostic information for patients with ovarian cancer is captured in clinico-genomic data, histopathology slides and computed tomography imaging; however, how to integrate these data is unclear. A study now presents a method for combining complementary data types to stratify risk and aid treatment selection in patients with ovarian cancer.

Melero and colleagues discuss the current landscape of immunotherapy combinations, ongoing clinical studies and the translational implications for efficacy and safety across tumor types.

Golub and colleagues identify the phosphate exporter XPR1 as a therapeutic vulnerability in ovarian and uterine cancers, and show that phosphate efflux inhibition reduces tumor cell viability through accumulation of intracellular phosphate.

Wu et al. utilize multiparametric analysis of early-stage human NSCLC to characterize a population of Vδ1 T cells displaying a resident memory and effector memory phenotype, which were associated with ongoing remission.

Hata and colleagues identify lorlatinib analogs that overcome acquired therapy resistance to current ALK inhibitors and show their efficacy in preclinical models of non-small cell lung cancer bearing compound therapy-resistant ALK alterations.

Shah and colleagues develop a multimodal data integration framework that interprets genomic, digital histopathology, radiomics and clinical data using machine learning to improve diagnosis of patients with high-grade ovarian serous carcinoma.

Weaver and colleagues use breast cancer patient-derived organoids and mouse models to find an inhibitory role for the nuclear repressor NCOR2 in chemotherapy response and antitumor immunity, which can be targeted by blocking NCOR2–HDAC3 interaction.

Na et al. identify KMT2C deficiency as a driver of small cell lung cancer metastasis and demonstrate that it leads to epigenetic reprogramming through histone and DNA hypomethylation by upregulating DNMT3A.

Using genome-wide bisulfite sequencing of acute lymphoblastic leukemia subtypes, cell lines and healthy cells, Hetzel et. al. find that unlike most cancers, ALL has a highly methylated genome, which points to a distinct mode of epigenome regulation in this cancer type.