Volume 4 Issue 5, May 2023

Elaine R. Mardis earned her PhD at the University of Oklahoma, in the laboratory of Bruce Roe. After postgraduate work at Bio-Rad Laboratories in California, she joined the Washington University School of Medicine faculty in 1993. In 2016, she moved to Nationwide Children’s Hospital and is a Professor of Pediatrics at The Ohio State University. She was elected to the US National Academy of Medicine in 2019.

Antigen presentation is fundamental to anti-tumor immunity, but our understanding of the physiological and molecular inputs to the process in different contexts remains limited. Two new studies explore the contribution of cell-intrinsic proteolytic mechanisms and cell-extrinsic hot and cold tumor microenvironments in shaping the antigenic landscape in lung cancer.

Glioblastomas have limited treatment options and dire prognoses. A study now shows that GAP43-mediated transfer of functional mitochondria from astrocytes to glioblastoma cells leads to metabolism, signaling and epigenome remodeling that favor tumor growth, thus highlighting GAP43 inhibition as a promising therapeutic strategy for glioblastoma.

Glioblastomas are aggressive primary brain tumors with an inherent resistance to T cell-centric immunotherapy. We examined the dynamic changes of immune cells that occur in the tumor microenvironment of radio-immunotherapy-treated glioblastomas and identified a subpopulation of regulatory T cells with increased immunosuppressive activity. Depletion of this cell population improved survival in a mouse model of glioblastoma.

An antisense RNA, NQO1-AS, binds and stabilizes its sense strand, upregulating the redox enzyme NQO1 in metastatic breast cancer cells. Overexpression of NQO1 facilitates lung colonization by suppressing oxidative stress and ferroptosis, and cancer cells dependent on this pathway can be targeted by a combined therapy that induces ferroptosis while simultaneously inhibiting NQO1.

Multiple myeloma is a rare and incurable cancer of plasma cells. To characterize this cancer, we developed an ex vivo drug screening method that combines imaging, deep learning and multiomics and applied it in an observational trial, uncovering new potential therapeutic strategies and underlying disease mechanisms.

Kimmelman and colleagues discuss the role of autophagy in tumor cells and of cell-nonautonomous autophagy in the microenvironment and host cells in supporting tumor growth and reflect on open questions in the field.

Bassani-Sternberg and colleagues perform multiregion immunopeptidomics, genomics and spatial transcriptomics in patient lung cancer samples, demonstrating heterogeneity in the immunopeptidome associated with degrees of immune cell infiltration.

Merbl and colleagues demonstrate that high expression of the proteasome regulator PSME4 is associated with immune-cold lung tumors and reduced antitumor immune responses, by functioning to modulate the protein degradome and antigen diversity.

Watson et al. demonstrate that astrocyte mitochondria can be horizontally transferred to glioblastoma cells in a GAP43-dependent manner, leading to changes in mitochondrial respiration and metabolism that promote proliferation and tumor growth.

Akkari and colleagues find that CD103⁺ regulatory T cells are highly abundant in the glioblastoma environment after checkpoint blockade restraining therapy response, and show therapeutic benefit for combined Treg targeting with radio-immunotherapy.

Culbertson et al. profile antisense RNAs using a newly developed computational pipeline and identify NQO1-AS as contributor to breast cancer progression and lung metastasis through regulation of the redox enzyme NQO1.

Beltran and colleagues examine the underlying mechanisms behind the observed heterogeneous expression of the prostate cancer drug target and biomarker, PSMA, in castration-resistant prostate cancer, involving regulatory roles of both HOXB13 and AR.

Sun et al. identify the deubiquitinase USP15 as a regulator of PARP1 stability in triple-negative breast cancer and show that the hormone receptors ER, PR and HER2 inhibit USP15-mediated PARP1 stabilization, modulating base excision repair.

Snijder and colleagues use ex vivo pharmacoscopy and bone marrow composition profiling in a cohort of patients with multiple myeloma to identify tailored therapeutic sensitivities and stratify the cohort into three microenvironmental PhenoGroups.

Mitsiades and colleagues utilize functional genomics data in over 700 cancer cell lines, to identify genes with preferentially essential functions in multiple myeloma, which may represent targets for precision medicine strategies.