Arbor G. Dykema

The role of glioma-associated myeloid cells in tumor growth and immune evasion remains poorly understood. We performed single-cell RNA sequencing of immune and tumor cells from 33 gliomas, identifying two distinct myeloid-derived suppressor cell (MDSC) populations in isocitrate dehydrogenase–wild-type (IDT-WT) glioblastoma: an early progenitor MDSC (E-MDSC) population with up-regulation of metabolic and hypoxia pathways and a monocytic MDSC (M-MDSC) population. Spatial transcriptomics demonstrated that E-MDSCs geographically colocalize with metabolic stem-like tumor cells in the pseudopalisading region. Ligand-receptor analysis revealed cross-talk between these cells, where glioma stem-like cells produce chemokines attracting E-MDSCs, which in turn produce growth factors for the tumor cells. This interaction is absent in IDH-mutant gliomas, associated with hypermethylation and repressed gene expression of MDSC-attracting chemokines. Our study elucidates specific MDSCs that may facilitate glioblastoma progression and mediate tumor immunosuppression.

Regulatory T cells (T_reg) are conventionally viewed as suppressors of endogenous and therapy-induced antitumor immunity; however, their role in modulating responses to immune checkpoint blockade (ICB) is unclear. In this study, we integrated single-cell RNA-seq/T cell receptor sequencing (TCRseq) of >73,000 tumor-infiltrating T_reg(TIL-T_reg) from anti–PD-1–treated and treatment-naive non–small cell lung cancers (NSCLC) with single-cell analysis of tumor-associated antigen (TAA)–specific T_regderived from a murine tumor model. We identified 10 subsets of human TIL-T_reg, most of which have high concordance with murine TIL-T_regsubsets. Only one subset selectively expresses high levels ofTNFRSF4(OX40) andTNFRSF18(GITR), whose engangement by cognate ligand mediated proliferative programs and NF-κB activation, as well as multiple genes involved in T_regsuppression, includingLAG3. Functionally, the OX40^hiGITR^hisubset is the most highly suppressive ex vivo, and its higher representation among total TIL-T_regcorrelated with resistance to PD-1 blockade. Unexpectedly, in the murine tumor model, we found that virtually all TIL-T_reg–expressing T cell receptors that are specific for TAA fully develop a distinct T_H1-like signature over a 2-week period after entry into the tumor, down-regulatingFoxP3and up-regulating expression ofTBX21 (Tbet), IFNG, and certain proinflammatory granzymes. Transfer learning of a gene score from the murine TAA-specific T_H1-like T_regsubset to the human single-cell dataset revealed a highly analogous subcluster that was enriched in anti–PD-1–responding tumors. These findings demonstrate that TIL-T_regpartition into multiple distinct transcriptionally defined subsets with potentially opposing effects on ICB-induced antitumor immunity and suggest that TAA-specific TIL-T_regmay positively contribute to antitumor responses.

Phenomenon: Despite a high degree of interest in research among matriculating M.D. students, very few apply to combined M.D.-Ph.D. training programs. Even fewer of those applicants are female, leading to a gender disparity among M.D.-Ph.D. trainees. We used a qualitative approach to understand why students choose not to apply or matriculate to M.D.-Ph.D. programs. Approach: We recruited recently matriculated medical students at a private research university with a self-reported interest in academic medicine and biomedical research to participate in focus groups, in which students discussed their career and life goals, general knowledge and sources of information for M.D.-Ph.D. programs, perceived benefits and downsides, and barriers to applying to such programs. Findings: Twenty-two students participated in focus groups. Participants desired careers combining clinical work, research, and teaching. Students had knowledge of the structure and goals of M.D.-Ph.D. training and received information about dual-degree programs from research mentors, the Internet, and peers. Tuition remission and increased grant access were cited as benefits of M.D.-Ph.D. programs, whereas duration, perceived excessive research training, and early commitment were downsides. Perceived competitiveness, misconceptions about training, a lack of M.D.-Ph.D. program-specific advising, discouragement from applying, and duration of training all served as barriers preventing students from pursuing dual-degree training. Insights: Through this qualitative study, we identified perceptions and misconceptions that recent medical school applicants have about M.D.-Ph.D. programs. These findings suggest targetable barriers to increase applications from interested students, such as improving awareness of programs, increased accessibility of advising and resources, and addressing concerns over training length, with the goal of improving training access for aspiring physician-scientists.

Antibodies that target immune checkpoint molecules, such as CTLA4, provide robust antitumor effects in a subset of patients. Unfortunately, not all patients respond to immune checkpoint inhibition, and some develop life-threatening immune-related adverse events (irAEs). The mechanisms that underlie irAEs from immune checkpoint inhibition are not fully understood, and treatment strategies are currently limited to targeting inflammatory mediators. In this issue of the JCI, Pai et al. report on their development of a modified CTLA4 antibody that shields the inner CTLA4-binding domain until the antibody is within the protease-rich tumor microenvironment. In a lymphopenic murine model reconstituted with naive CD4(+) T cells, adapted anti-CTLA4 reduced the occurrence of irAEs and enhanced antitumor effects. This thought-provoking study lays the groundwork for further exploration of this adapted antibody in immunocompetent hosts and introduction of this adaptation to other immune checkpoint molecules. It also suggests that this approach may reduce the incidence of irAEs.