Highlights of This Issue Free

The BIM deletion polymorphism is associated with apoptosis resistance to EGFR-TKIs, such as gefitinib and erlotinib, in EGFR mutated lung cancer. Tanimoto and colleagues report that the BIM deletion polymorphism is sufficient to confer resistance to the third-generation TKI, osimertinib. They further identified HDAC3 as an important regulator of BIM pre-mRNA splicing, and that pan-HDAC inhibitor vorinostat overcomes BIM deletion polymorphism associated EGFR-TKI resistance via inhibition of HDAC3. These findings illustrate the importance of developing selective HDAC3 inhibitors, and provide the rationale for combined use of HDAC3 inhibitors with osimertinib in EGFR-mutated lung cancer carrying the BIM deletion polymorphism.

The mechanisms that allow tumor cells to escape immunosurveillance are not well understood. Pereira and colleagues found recurrent inactivating mutations in the invariant light chain of the HLA-I complex, B2M in lung cancer. Furthermore, they found alterations at CALR, PDIA3, and TAP1, which are involved in the maturation of the HLA-I complex. Downregulation of the HLA-I complex was associated with low cytotoxic CD8⁺ lymphocyte infiltration and low expression of PD-L1, evidencing an abnormal immunosurveillance axis. The authors also provide preliminary observations showing that alterations at the HLA-I complex affect responsiveness to anti-PD-1/anti-PD-L1 therapies in lung cancer patients.

Over the past 15 years there have been conflicting reports of cytomegalovirus (CMV) detection in glioblastomas (GBM) and other high-grade gliomas (HGG). The detection of CMV in GBM prompted clinical studies and resources to determine the role of antiviral or CMV-based immunotherapies in these tumors. Holdhoff and colleagues report on the absence of CMV in GBM/HGG tissues using three different technologies to detect CMV DNA and protein. These findings provide additional evidence for a lack of CMV in GBM/HGG and call for a final multi-center blinded analysis to provide definitive guidance for investigators in this field.

Anti-PD-1 therapies are effective in ∼40% of patients with metastatic melanoma; however, the majority of melanomas are treatment-resistant. Studies of melanoma response/resistance in living patients are facilitated by the frequent occurrence of superficial cutaneous and lymph node metastases amenable to biopsy, but they are limited by the typically small volumes of these disease sites and the inaccessibility of visceral metastases. Ascierto and colleagues conducted the rapid autopsy of an individual with widespread melanoma experiencing a mixed response to anti–PD-1 therapy to explore anti–PD-1 response/resistance concordantly at the genetic, immunological, and transcriptional levels. A distinct gene expression profile was associated with progressing metastases, suggesting that nongenomic transcriptional programs can determine outcomes to anti–PD-1 therapy.