See article by Josefsson et al., p. 870

T cells infiltrating follicular lymphoma (FL) tumors are considered dysfunctional, yet the optimal target for checkpoint inhibition is unknown. To identify new targets for checkpoint blockade, Josefsson and colleagues combined in-depth characterization of coinhibitory receptor expression with measurement of T-cell receptor (TCR)-induced signaling responses. This approach successfully identified TIGIT as the main immune checkpoint receptor in dysfunctional FL T cells, and thus provided new insights into clinically relevant mechanisms that may contribute to immunosuppression in FL. The potential relevance of TIGIT inhibition as a novel form of checkpoint therapy is high and support clinical investigation of TIGIT blockade in FL.

See article by Luraghi et al., p. 807

Reliable preclinical models are needed to speed-up the clinical development of new effective cancer therapies. A large collection of metastatic colorectal cancer xenopatients has been successfully exploited to identify new genetic mechanisms of resistance to the anti-EGFR antibody cetuximab and to prove the efficacy of new treatment strategies. From xenopatients, Luraghi and colleagues derived an ample collection of stem-like cultures (xenospheres), faithfully mirroring the genetic, biological, and pharmacologic properties of xenopatients. Xenospheres offer the unique opportunity to study in vitro and in vivo nongenetic mechanisms of resistance that can be underestimated in xenopatients. Through this approach, the authors provide robust preclinical evidence that NRG1 is a crucial biomarker to predict both cetuximab resistance in the absence of genetic mechanisms and response to pan-HER inhibition. Xenospheres are thus a reliable patient-derived in vitro model required to complement xenopatients in elucidating the mechanisms of response to targeted therapies in metastatic colorectal cancer.

See article by Nandhu et al., p. 821

The molecular heterogeneity and invasive ability of glioblastoma (GBM) cells are two major obstacles for successful therapy of these malignant brain cancers. Targeting the tumor extracellular matrix (ECM) may help overcome these obstacles because ECM molecules secreted by tumor cells are necessary for invasion and relatively conserved across the tumor parenchyma. New strategies against the ECM must first identify functional domains in ECM targets and develop reagents to block those domains and disrupt signaling initiated and regulated by ECM molecules. Nandhu and colleagues developed a function-blocking antibody against a GBM-enriched ECM protein (fibulin-3) that is a "first in class" reagent able to inhibit protumoral signaling and reduce GBM progression. Anti-ECM reagents may exploit a niche that is currently underexplored, leading towards more efficient combination treatments for GBM and potentially other solid tumors.

See article by Li et al., p. 906

To identify novel loci for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), Li and colleagues performed a genome-wide association study (GWAS) among the Chinese. The variants at 7q21.13 locus were revealed to confer both increased susceptibility and worse prognosis to HBV-related HCC. Furthermore, the cyclin-dependent kinase 14 (CDK14) was suggested to be the causative gene at 7q21.13. These findings expand the understanding of the genetic susceptibility to HBV-related HCC and highlight the relevance of CDK14 as a novel therapeutic target for HCC by CDK inhibitors.