Volume 4 Issue 8, August 2023

T cell-based immunotherapies have revolutionized cancer treatment, and strategies to redirect T cells to recognize cancer cells are being investigated both preclinically and clinically. Bispecific T cell-engagers are antibodies that simultaneously bind to an antigen on tumor cells and a surface molecule on T cells. They have shown impressive activity in B cell malignancies and are being explored in many other cancer entities.

Distinct subsets of γδ T cells that operate to either prevent or promote cancer progression have been characterized in mice. A study now indicates that human tumor-infiltrating γδ T cells also are more diverse than previously appreciated, consisting of functionally distinct subsets with tumor-promoting or -restricting functions.

The advantage of genomic monitoring over cytogenetics for clinical assessment of leukemia is illustrated by a case of pediatric acute lymphoblastic leukemia in which a lesion underlying lethal end-stage myeloid disease could be detected by whole-genome sequencing years before the risk manifested cytogenetically.

The recent design of mutation-selective KRAS inhibitors has led to US Food and Drug Administration approval of two inhibitors of KRAS(G12C), sotorasib and adagrasib. A study published in Nature reports the development of a first-in-class pan-KRAS-selective inhibitor. Here we comment on the current status of KRAS-targeting approaches.

Blanpain and colleagues review the current knowledge on cancer cell plasticity and its impact on tumor initiation and progression, the metastatic cascade and resistance to therapy.

Sears and colleagues discuss the latest advances in the understanding of host and microbiota mechanisms involved in the relationship between the microbiome and cancer and emerging avenues for applying these insights to cancer therapy.

Coorens et. al. perform whole-genome sequencing and phylogenetic analyses in a child patient with leukemia that underwent lineage switch following therapy, finding that the AML arose from a pre-existing clone, rather than the most recent ALL relapse.

Alimonti and colleagues show that coordinated activation of the Akt/mTOR and MNK/eIF4E pathways rewires the prostate cancer translatome to secrete HGF, SPP1 and BGN and recruit suppressive myeloid cells, which can be therapeutically targeted.

Lynch and colleagues characterize γδ T cells in colorectal and endometrial cancer and identify distinct subsets with opposing cytotoxic and wound healing functions, leading them to develop an expansion method that enhances cytotoxic functions.

Wang and colleagues perform single-cell profiling of human ovarian cancer samples from five anatomic sites, revealing dynamics of the immune microenvironment in malignant ascites and cell subtypes that may play a role in chemotherapy response.

Guccione and colleagues identify and characterize a sorafenib derivative, WNTinib, with therapeutic efficacy in β-catenin-mutated hepatocellular carcinoma and identify EZH2 as important for the activity of the inhibitor.

Wang and colleagues generate two protein-level mutant p53 reporters and use them to identify precancerous clones in normal tissues in vivo, characterized by increased amino acid metabolism and a transcriptomic signature that includes Ybx3.

Grockowiak et al. explore bone marrow niche heterogeneity in myeloproliferative neoplasms, polycytemia vera and essential thrombocytemia and find JAK2-mutated hematopoietic stem cells occupying distinct niches affecting cell growth and therapy response.