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The CD58-CD2 axis regulates T cell-mediated cancer immunity, but little is known about the regulation of CD58. In two recent papers pubished in Cancer Cell , Miao et al. and Ho et al. define a mechanism of CD58 regulation by CMTM6 and show an unexpected yin-yang link between PD-L1 and CD58. The CD58-CD2 axis regulates T cell-mediated cancer immunity, but little is known about the regulation of CD58. In two recent papers published in Cancer Cell , Miao et al. and Ho et al. define a mechanism of CD58 regulation by CMTM6 and show an unexpected yin-yang link between PD-L1 and CD58. [ABSTRACT FROM AUTHOR]

Cytotoxic T lymphocytes recognize and kill cancer cells when the latter present antigenic epitopes complexed with MHC class I molecules on their surface. In a recent Science paper, Mangalhara et al. show that alterations of the mitochondrial electron flow upregulate multiple factors involved in antigen presentation via a succinate-dependent epigenetic mechanism. Cytotoxic T lymphocytes recognize and kill cancer cells when the latter present antigenic epitopes complexed with MHC class I molecules on their surface. In a Science paper, Mangalhara et al. show that alterations of the mitochondrial electron flow upregulate multiple factors involved in antigen presentation via a succinate-dependent epigenetic mechanism. [ABSTRACT FROM AUTHOR]

Drugs that target KRAS 12C covalently, AMG 510 and MRTX849, are now in the clinic. Recent papers describe development of these compounds, their selectivity and properties, early clinical data, and potential combination therapies. These papers herald a new era in Ras research, with improved drugs and strategies certain to follow.

Two papers published in this edition of Cancer Cell (Zheng et al., 2022 and Veatch et al., 2022) provide an elegant illustration of how single-cell sequencing can be used to define a molecular phenotype which identifies tumor-specific T cells. Two papers published in this edition of Cancer Cell (Zheng et al., 2022 and Veatch et al., 2022) provide an elegant illustration of how single-cell sequencing can be used to define a molecular phenotype which identifies tumor-specific T cells. [ABSTRACT FROM AUTHOR]

In this Q&A, Cell Press Community Review Scientific Editor Leia Judge talks to Dr. Clint Allen and Dr. Sandro Santagata about their new papers "Phenotypic plasticity and reduced tissue retention of exhausted tumor-infiltrating T cells following neoadjuvant immunotherapy in head and neck cancer" and "Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma" and their experiences with publishing through Cell Press Community Review. [ABSTRACT FROM AUTHOR]

The immune system employs complex tolerance mechanisms in order to avoid harmful autoimmunity, yet autoantibodies are frequently observed in cancer. In a paper in Cell , Mazor et al. report that autoantibodies produced by tumor-infiltrating B cells in human ovarian cancer frequently recognize the self-protein matrix metalloproteinase 14 (MMP14) through two distinct mechanisms of tolerance disruption. [ABSTRACT FROM AUTHOR]

Discrete tissue niches are emerging as essential prerequisites enabling cell communication and function in both homeostasis and disease. In a recent Cell paper, Di Pilato et al. identify a unique dendritic cell-cytotoxic T cell crosstalk within the perivascular space that facilitates T cell survival and proliferation and drives anti-tumor activity. [ABSTRACT FROM AUTHOR]

Eligibility criteria restrict patient enrollment in clinical trials. A Nature paper applied a machine-learning algorithm in a real-world database to show that relaxing some criteria may not jeopardize efficacy and safety. This may enable more patients to have earlier access to new therapies and make results more generalizable to clinical practice. [ABSTRACT FROM AUTHOR]

The functional repertoire of intratumoral microorganisms and their local effects on the host remain poorly characterized. By revealing potentially immunogenic bacterial peptides on melanoma cells, a Nature paper provides evidence that intratumoral bacteria can directly modulate antitumor immune responses, and it details a new class of therapeutically relevant, non-human tumor antigens. [ABSTRACT FROM AUTHOR]

Two recent Lancet and Lancet Oncology papers report that cancer patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have higher mortality rates. Common independent factors associated with increased risk of death were older age, history of smoking status, number of comorbidities, more advanced performance status, and active cancer. [ABSTRACT FROM AUTHOR]

A paper published in Science probes over 1500 tumor samples from multiple cancer types for markers of a tumor microbiome and viable bacteria. Unique intertumoral and intracellular signatures associated with clinical biomarkers and metabolic pathways provide clues to the roles bacteria play in carcinogenesis. [ABSTRACT FROM AUTHOR]

Reprogramming the tumor microenvironment may be a key strategy to broaden the efficacy of current cancer immunotherapies. In a recent Nature paper, Canale et al. use synthetic biology to alter intratumoral arginine levels via engineered bacteria, leading to improved responsiveness to anti-PD-L1 checkpoint blockade in a murine model of cancer. [ABSTRACT FROM AUTHOR]

Two papers published recently in the New England Journal of Medicine describe the utility of abiraterone acetate, an androgen biosynthesis inhibitor, in the early treatment of metastatic prostate cancer. In addition to establishing a new standard of care, these two articles pose a number of important questions for future investigation. [ABSTRACT FROM AUTHOR]

Effective cancer therapy requires that a cancer be more susceptible to a treatment than are the essential tissues in the body. A paper by Sarosiek et al. in this issue now shows that, unlike those of cancer cells, mitochondria in many tissues in adults are in an apoptosis-resistant state. [ABSTRACT FROM AUTHOR]

In a recent Nature paper, Yamamoto et al. demonstrate that, in the particular context of pancreatic carcinoma, autophagy causes the continuous destruction of major histocompatibility complex class I (MHC-I) proteins. Suppression of autophagy favors MHC-I re-appearance on the surface of malignant cells, facilitating their clearance by cytotoxic T lymphocytes. [ABSTRACT FROM AUTHOR]

The mechanisms through which tumor antigen-specific T cells are elicited in natural or chemotherapy-induced immunosurveillance have been elusive. In this issue of Cancer Cell , two papers by Broz and colleagues and Ruffell and colleagues delineate an important role for a specific dendritic cell subset characterized by CD103 expression, dependence on transcription factors Batf3 and Irf8, and interleukin-12 production. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma, even when diagnosed early, nearly always metastasizes. Recurrent mutations and genomic instability are early events in the disease. Two recent papers advance our understanding of how the cancer genome evolves as the primary tumor migrates from its origin in the pancreas to colonize distant metastatic sites. [ABSTRACT FROM AUTHOR]

Glioma-associated mutations in IDH1 or IDH2 lead to aberrant DNA methylation. A recent paper shows that loss of methylation-sensitive CTCF binding in IDH mutant cells leads to disruption of enhancer boundary function, which results in aberrant activation of PDGFRA expression via an enhancer associated with an adjacent gene. [ABSTRACT FROM AUTHOR]

Inhibitors of B cell receptor signaling substantially changed the treatment of chronic lymphocytic leukemia as the first targeted agents to enter routine clinical practice. A recent paper by Roberts and colleagues describes an additional therapeutic target by reporting encouraging clinical results with venetoclax, an inhibitor of the antiapoptotic protein BCL2. [ABSTRACT FROM AUTHOR]

Mutations in the TP53 gene not only inactivate its tumor suppressor function but also confer this transcription factor with gain-of-function oncogenic properties. A recent paper by Zhu and colleagues reveals a novel molecular pathway driven by mutant p53 and the COMPASS chromatin-modifying complex that is amenable to pharmacological inhibition. [ABSTRACT FROM AUTHOR]

In this issue of Cancer Cell , two complementary papers by Atwood and colleagues and Sharpe and colleagues show that basal cell carcinomas resistant to the Smoothened (SMO) inhibitor vismodegib frequently harbor SMO mutations that limit drug binding, with mutations at some sites also increasing basal SMO activity. [ABSTRACT FROM AUTHOR]

In a Science paper, Park et al. identified interleukin (IL)-1α as a key driver of positive feedback in inflammaging, linking aging-associated downregulation of DNMT3A to increased IL-1α production in lung myeloid cells. This triggers emergency myelopoiesis in the bone marrow, amplifying myeloid-mediated intratumoral immunosuppression for tumor progression in aged mice., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In this issue of Cancer Cell, Espinosa-Carrasco et al. show that the efficacy of cancer immunotherapies depends upon the formation of intratumoral immune triads between antigen-presenting cells and antigen-specific CD4 + and CD8 + T cells. This interaction reprograms tumor-specific CD8 + T cells to exert potent effector functions and eradicate established solid tumors., Competing Interests: Declaration of interests E.L. received research grants from Bristol Myers Squibb on a topic unrelated to this paper, royalties from the NIH for a patent on methods to develop T memory stem cells, and consulting fees from BD Biosciences, Biolegend, Swarm Therapeutics, Menarini, Amgen, and Pfizer., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Fusion-transcription factors (fusion-TFs) represent a class of driver oncoproteins that are difficult to therapeutically target. Recently, protein degradation has emerged as a strategy to target these challenging oncoproteins. The mechanisms that regulate fusion-TF stability, however, are generally unknown. Using CRISPR-Cas9 screening, we discovered tripartite motif-containing 8 (TRIM8) as an E3 ubiquitin ligase that ubiquitinates and degrades EWS/FLI, a driver fusion-TF in Ewing sarcoma. Moreover, we identified TRIM8 as a selective dependency in Ewing sarcoma compared with >700 other cancer cell lines. Mechanistically, TRIM8 knockout led to an increase in EWS/FLI protein levels that was not tolerated. EWS/FLI acts as a neomorphic substrate for TRIM8, defining the selective nature of the dependency. Our results demonstrate that fusion-TF protein stability is tightly regulated and highlight fusion oncoprotein-specific regulators as selective therapeutic targets. This study provides a tractable strategy to therapeutically exploit oncogene overdose in Ewing sarcoma and potentially other fusion-TF-driven cancers., Competing Interests: Declaration of interests K.S. has funding from Novartis Institutes for BioMedical Research, consults for and has stock options in Auron Therapeutics and served as an advisor for Kronos Bio and AstraZeneca all on topics unrelated to this manuscript. E.S.F. is a founder, scientific advisory board (SAB) member, and equity holder of Civetta Therapeutics, Jengu Therapeutics (board member), and Neomorph Inc., an equity holder in C4 Therapeutics, and is a consultant to Novartis, Sanofi, EcoR1 capital, Astellas, and Deerfield. The Fischer lab receives or has received research funding from Novartis, Ajax, Deerfield, and Astellas on topics unrelated to this manuscript. B.N. is an inventor on patent applications related to the dTAG system (WO/2017/024318, WO/2017/024319, WO/2018/148440, and WO/2018/148443). F.M.F., B.N., and N.S.G. are inventors on a patent related to the dTAG system and molecules described in this manuscript (WO/2020/146250). F.M.F. is a consultant to RA Capital and Santi Therapeutics. N.S.G. is a founder, SAB member and equity holder in Syros, C4, Allorion, Jengu, B2S, Inception, EoCys, Larkspur (board member), and Soltego (board member). The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Jansen, Kinogen, Arbella, Deerfield, and Sanofi on topics unrelated to this manuscript. N.V.D. is a current employee of Genentech, Inc., a member of the Roche Group. K.A.D. is a consultant to Kronos Bio. Inclusion and diversity One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. One or more of the authors of this paper received support from a program designed to increase minority representation in science., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Adoptive cell immunotherapy using in vitro expanded autologous tumor-infiltrating lymphocytes has the potential to mediate durable remission of certain types of cancer. A recent paper in Science shows that complete and durable control of metastatic melanoma requires the infusion of tumor-specific CD8 + T cells that have stem-cell-like properties., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Abundant neoantigens are considered responsible for the immunotherapy sensitivity of mismatch repair-deficient (MMRd) cancers. In this issue of Cancer Cell, two papers show that MLH1 mismatch repair gene loss promotes cGAS-STING activation, interferon secretion, and T cell priming. This may be essential for the high immunotherapy sensitivity in MMRd cancer., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Certain Protein Phosphatase 2A (PP2A) complexes are human tumor suppressors. In contrast, a paper in this issue of Cancer Cell and two other recent studies demonstrate that PP2A-STRN3/4 complexes inactivate Hippo tumor suppressor pathway, resulting in YAP activation and tumorigenesis. Furthermore, this new oncogenic phosphatase mechanism may be druggable., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Two papers, published in Science and Nature, report inhibitiors selectively targeting distinct bromodomains of BET proteins. These advanced chemical tools facilitate functional understanding of epigenetic regulators in normal and disease states and enable development of new medicine potentially with lower toxicity., Competing Interests: Declaration of Interests J.Q. is a scientific co-founder and consultant for Epiphanes and is a shareholder of Zentalis. Y.S. is a scientific co-founder and equity holder of Constellation Pharmaceuticals and Athelas Therapeutics, an equity holder of Imago Biosciences, and a consultant for Active Motif., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In a recently published Cell paper, Roth et al. report a CRISPR-based platform for developing T cell therapies that strategically combine a tumor-specific TCR with novel protein factors that potentiate antitumor function., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Recent clinical trials in cancer therapy have demonstrated unprecedented responses through blockade of CTLA-4 and PD-1 immune checkpoint pathways. In a provocative recent paper in Science Translational Medicine, Hatfield and colleagues demonstrate the ability of supplemental oxygen to act as a novel immune checkpoint inhibitor by disrupting the hypoxia-adenosine-A2aR pathway., (Copyright © 2015 Elsevier Inc. All rights reserved.)