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Immunosuppressive macrophages restrict anti-cancer immunity in glioblastoma (GBM). Here, we studied the contribution of microglia (MGs) and monocyte-derived macrophages (MDMs) to immunosuppression and mechanisms underlying their regulatory function. MDMs outnumbered MGs at late tumor stages and suppressed T cell activity. Molecular and functional analysis identified a population of glycolytic MDM expressing GLUT1 with potent immunosuppressive activity. GBM-derived factors promoted high glycolysis, lactate, and interleukin-10 (IL-10) production in MDMs. Inhibition of glycolysis or lactate production in MDMs impaired IL-10 expression and T cell suppression. Mechanistically, intracellular lactate-driven histone lactylation promoted IL-10 expression, which was required to suppress T cell activity. GLUT1 expression on MDMs was induced downstream of tumor-derived factors that activated the PERK-ATF4 axis. PERK deletion in MDM abrogated histone lactylation, led to the accumulation of intratumoral T cells and tumor growth delay, and, in combination with immunotherapy, blocked GBM progression. Thus, PERK-driven glucose metabolism promotes MDM immunosuppressive activity via histone lactylation. [Display omitted] • Glycolytic MDMs are major contributors to the immunosuppression associated with TAMs • Intracellular lactate regulates IL-10 expression in MDMs via histone lactylation • PERK supports glucose metabolism in MDMs and regulates GLUT1 expression through ATF4 • PERK targeting blocks GBM progression in combination with immunotherapy There are no effective approaches to overcome the immunosuppressive activity of tumor-associated macrophages (TAMs). De Leo et al. report that monocyte-derived macrophages (MDMs), but not microglia (MGs), are major contributors to the immunosuppression associated with TAMs in glioblastoma and demonstrate that PERK-perturbed glucose metabolism drives MDM immunosuppressive programs via histone lactylation. Targeting of PERK-driven histone lactylation boosts the effect of immunotherapy. [ABSTRACT FROM AUTHOR]

Summary Adaptation of malignant cells to the hostile milieu present in tumors is an important determinant of their survival and growth. However, the interaction between tumor-linked stress and antitumor immunity remains poorly characterized. Here, we show the critical role of the cellular stress sensor C/EBP-homologous protein (Chop) in the accumulation and immune inhibitory activity of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). MDSCs lacking Chop had decreased immune-regulatory functions and showed the ability to prime T cell function and induce antitumor responses. Chop expression in MDSCs was induced by tumor-linked reactive oxygen and nitrogen species and regulated by the activating-transcription factor-4. Chop-deficient MDSCs displayed reduced signaling through CCAAT/enhancer-binding protein-β, leading to a decreased production of interleukin-6 (IL-6) and low expression of phospho-STAT3. IL-6 overexpression restored immune-suppressive activity of Chop-deficient MDSCs. These findings suggest the role of Chop in tumor-induced tolerance and the therapeutic potential of targeting Chop in MDSCs for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Monocytic-lineage inflammatory Ly6c+CD103+ dendritic cells (DCs) promote antitumor immunity, but these DCs are infrequent in tumors, even upon chemotherapy. Here, we examined how targeting pathways that inhibit the differentiation of inflammatory myeloid cells affect antitumor immunity. Pharmacologic inhibition of Bruton's tyrosine kinase (BTK) and the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) or deletion of Btk or Ido1 allowed robust differentiation of inflammatory Ly6c+CD103+ DCs during chemotherapy, promoting antitumor T cell responses and inhibiting tumor growth. Immature Ly6c+c-kit+ precursor cells had epigenetic profiles similar to conventional DC precursors; deletion of Btk or Ido1 promoted differentiation of these cells. Mechanistically, a BTK-IDO axis inhibited a tryptophan-sensitive differentiation pathway driven by GATOR2 and mTORC1, and disruption of the GATOR2 in monocyte-lineage precursors prevented differentiation into inflammatory DCs in vivo. IDO-expressing DCs and monocytic cells were present across a range of human tumors. Thus, a BTK-IDO axis represses differentiation of inflammatory DCs during chemotherapy, with implications for targeted therapies. [Display omitted] • Certain DC precursors in mouse tumors co-express BTK and IDO • The BTK-IDO pathway inhibits mTORC1 signaling and suppresses DC differentiation • Blocking BTK and IDO during chemotherapy synergistically enhances immune activation • DCs expressing BTK and IDO are present in a variety of human tumors Dendritic cells (DCs) in tumors are often dysfunctional, failing to effectively cross-present tumor antigens following chemotherapy. Sharma et al. reveal a pathway consisting of the kinase BTK and the tryptophan-depleting enzyme IDO that suppresses the activation of monocyte-lineage DCs by inhibiting amino acid-sensitive mTORC1 signaling. Pharmacological blockade of this pathway promotes the differentiation of inflammatory DCs and enhances antitumor T cells responses. [ABSTRACT FROM AUTHOR]

Blockade of the inhibitory receptor TIM-3 shows efficacy in cancer immunotherapy clinical trials. TIM-3 inhibits production of the chemokine CXCL9 by XCR1+ classical dendritic cells (cDC1), thereby limiting antitumor immunity in mammary carcinomas. We found that increased CXCL9 expression by splenic cDC1s upon TIM-3 blockade required type I interferons and extracellular DNA. Chemokine expression as well as combinatorial efficacy of TIM-3 blockade and paclitaxel chemotherapy were impaired by deletion of Cgas and Sting. TIM-3 blockade increased uptake of extracellular DNA by cDC1 through an endocytic process that resulted in cytoplasmic localization. DNA uptake and efficacy of TIM-3 blockade required DNA binding by HMGB1, while galectin-9-induced cell surface clustering of TIM-3 was necessary for its suppressive function. Human peripheral blood cDC1s also took up extracellular DNA upon TIM-3 blockade. Thus, TIM-3 regulates endocytosis of extracellular DNA and activation of the cytoplasmic DNA sensing cGAS-STING pathway in cDC1s, with implications for understanding the mechanisms underlying TIM-3 immunotherapy. [Display omitted] • TIM-3 blockade promotes endocytosis of extracellular DNA by dendritic cells • DNA uptake and CXCL9 expression by dendritic cells is HMGB1 dependent • Galectin-9 regulates TIM-3 cell surface clustering and inhibitory function • Antitumor efficacy of TIM-3 mAb and paclitaxel is dependent upon cGAS and STING Blockade of the inhibitory receptor TIM-3 shows efficacy in cancer immunotherapy clinical trials. de Mingo Pulido et al. provide insight into the underlying mechanisms by revealing that TIM-3 suppresses HMGB1-dependent endocytosis of extracellular DNA and the subsequent activation of the cGAS-STING pathway in intra-tumoral dendritic cells. [ABSTRACT FROM AUTHOR]

Gamma-delta T cells (γδ T cells) play a crucial role in both innate and adaptive immunity within tumors, yet their presence and prognostic value in cancer remain underexplored. This study presents a large-scale analysis of γδ T cell receptor (γδ TCR) reads from 11,000 tumor samples spanning 33 cancer types, utilizing the TRUST4 algorithm. Our findings reveal extensive diversity in γδ TCR clonality and gene expression, underscoring the potential of γδ T cells as prognostic biomarkers in various cancers. We further demonstrate the utility of TCR gamma (TRG) and delta (TRD) gene expression from standard RNA-sequencing (RNA-seq) data. This comprehensive dataset offers a valuable resource for advancing γδ T cell research, with implications for enhanced immunotherapy approaches or alternative therapeutic strategies. Additionally, our centralized database supports translational research into the therapeutic significance of γδ T cells., Competing Interests: Declaration of interests J.R.C.-G. is a consultant for Anixa Biosciences and Alloy Therapeutics; holds stock options in Compass Therapeutics, Anixa Biosciences, and Alloy Therapeutics; has a patent licensed by Anixa Biosciences; owns intellectual property filed with Compass Therapeutics; and is a co-founder of Cellepus Therapeutics, a CAR T cell company., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Signaling through Notch receptors intrinsically regulates tumor cell development and growth. Here, we studied the role of the Notch ligand Jagged2 on immune evasion in non-small cell lung cancer (NSCLC). Higher expression of JAG2 in NSCLC negatively correlated with survival. In NSCLC pre-clinical models, deletion of Jag2, but not Jag1, in cancer cells attenuated tumor growth and activated protective anti-tumor T cell responses. Jag2 -/- lung tumors exhibited higher frequencies of macrophages that expressed immunostimulatory mediators and triggered T cell-dependent anti-tumor immunity. Mechanistically, Jag2 ablation promoted Nr4a-mediated induction of Notch ligands DLL1/4 on cancer cells. DLL1/4-initiated Notch1/2 signaling in macrophages induced the expression of transcription factor IRF4 and macrophage immunostimulatory functionality. IRF4 expression was required for the anti-tumor effects of Jag2 deletion in lung tumors. Antibody targeting of Jagged2 inhibited tumor growth and activated IRF4-driven macrophage-mediated anti-tumor immunity. Thus, Jagged2 orchestrates immunosuppressive systems in NSCLC that can be overcome to incite macrophage-mediated anti-tumor immunity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Dimeric IgA (dIgA) can move through cells via the IgA/IgM polymeric immunoglobulin receptor (PIGR), which is expressed mainly on mucosal epithelia. Here, we studied the ability of dIgA to target commonly mutated cytoplasmic oncodrivers. Mutation-specific dIgA, but not IgG, neutralized KRAS G12D within ovarian carcinoma cells and expelled this oncodriver from tumor cells. dIgA binding changed endosomal trafficking of KRAS G12D from accumulation in recycling endosomes to aggregation in the early/late endosomes through which dIgA transcytoses. dIgA targeting of KRAS G12D abrogated tumor cell proliferation in cell culture assays. In vivo, KRAS G12D -specific dIgA1 limited the growth of KRAS G12D -mutated ovarian and lung carcinomas in a manner dependent on CD8 + T cells. dIgA specific for IDH1 R132H reduced colon cancer growth, demonstrating effective targeting of a cytoplasmic oncodriver not associated with surface receptors. dIgA targeting of KRAS G12D restricted tumor growth more effectively than small-molecule KRAS G12D inhibitors, supporting the potential of this approach for the treatment of human cancers., Competing Interests: Declaration of interests J.R.C.-G. has stock options in Compass Therapeutics, Anixa Biosciences, and Alloy Therapeutics; has sponsored research with Anixa Biosciences; receives honorarium from Alloy Therapeutics; and has intellectual property with Compass Therapeutics and Anixa Biosciences; all outside the submitted work. J.R.C.-G. and S.B. have filed a patent application for intracellular targeting of oncodrivers using dIgA. B.A.P. has completed Advisory Board with AstraZeneca and has Research Support from BMS. R.L.: clinical trial protocol committee—CG Oncology; Scientific adviser/consultant—BMS, Ferring, Fergene, Arquer Diagnostics., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Low response rates and immune-related adverse events limit the remarkable impact of cancer immunotherapy. To improve clinical outcomes, preclinical studies have shown that combining immunotherapies with N-terminal Hsp90 inhibitors resulted in improved efficacy, even though induction of an extensive heat shock response (HSR) and less than optimal dosing of these inhibitors limited their clinical efficacy as monotherapies. We discovered that the natural product Enniatin A (EnnA) targets Hsp90 and destabilizes its client oncoproteins without inducing an HSR. EnnA triggers immunogenic cell death in triple-negative breast cancer (TNBC) syngeneic mouse models and exhibits superior antitumor activity compared to Hsp90 N-terminal inhibitors. EnnA reprograms the tumor microenvironment (TME) to promote CD8 + T cell-dependent antitumor immunity by reducing PD-L1 levels and activating the chemokine receptor CX3CR1 pathway. These findings provide strong evidence for transforming the immunosuppressive TME into a more tumor-hostile milieu by engaging Hsp90 with therapeutic agents involving novel mechanisms of action., Competing Interests: A.C. and Augusta University have a patent (US 11,446,352 B2) related to this work. All other authors have no conflict of interest to declare for this research., (© 2023 The Authors.)

The tumor microenvironment (TME) provokes endoplasmic reticulum (ER) stress in malignant cells and infiltrating immune populations. Sensing and responding to ER stress is coordinated by the unfolded protein response (UPR), an integrated signaling pathway governed by three ER stress sensors: activating transcription factor (ATF6), inositol-requiring enzyme 1α (IRE1α), and protein kinase R (PKR)-like ER kinase (PERK). Persistent UPR activation modulates malignant progression, tumor growth, metastasis, and protective antitumor immunity. Hence, therapies targeting ER stress signaling can be harnessed to elicit direct tumor killing and concomitant anticancer immunity. We highlight recent findings on the role of the ER stress responses in onco-immunology, with an emphasis on genetic vulnerabilities that render tumors highly sensitive to therapeutic UPR modulation., Competing Interests: Declaration of interests J.R.C-R. is a scientific consultant for NextRNA Therapeutics, Inc. and Autoimmunity Biologic Solutions, Inc. P.R. and J.R.C-R. hold patents on targeting ER stress pathways for the treatment of disease. The other authors declare no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Activation of unfolded protein responses (UPRs) in cancer cells undergoing endoplasmic reticulum (ER) stress promotes survival. However, how UPR in tumor cells impacts anti-tumor immune responses remains poorly described. Here, we investigate the role of the UPR mediator pancreatic ER kinase (PKR)-like ER kinase (PERK) in cancer cells in the modulation of anti-tumor immunity. Deletion of PERK in cancer cells or pharmacological inhibition of PERK in melanoma-bearing mice incites robust activation of anti-tumor T cell immunity and attenuates tumor growth. PERK elimination in ER-stressed malignant cells triggers SEC61β-induced paraptosis, thereby promoting immunogenic cell death (ICD) and systemic anti-tumor responses. ICD induction in PERK-ablated tumors stimulates type I interferon production in dendritic cells (DCs), which primes CCR2-dependent tumor trafficking of common-monocytic precursors and their intra-tumor commitment into monocytic-lineage inflammatory Ly6C + CD103 + DCs. These findings identify how tumor cell-derived PERK promotes immune evasion and highlight the potential of PERK-targeting therapies in cancer immunotherapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In this issue of Cancer Cell, Long et al. demonstrate that tumors can reprogram erythroid progenitors into myeloid-erythroid cells that promote immunosuppression. Erythroid-differentiated myeloid cells (EDMCs) expand in cancer-bearing individuals, resemble the functionality of myeloid-derived suppressor cells (MDSCs), and correlate with poor response to immune-checkpoint inhibitors (ICIs) and tumor-related anemia., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Despite repeated associations between T cell infiltration and outcome, human ovarian cancer remains poorly responsive to immunotherapy. We report that the hallmarks of tumor recognition in ovarian cancer-infiltrating T cells are primarily restricted to tissue-resident memory (TRM) cells. Single-cell RNA/TCR/ATAC sequencing of 83,454 CD3 + CD8 + CD103 + CD69 + TRM cells and immunohistochemistry of 122 high-grade serous ovarian cancers shows that only progenitor (TCF1 low ) tissue-resident T cells (TRM stem cells), but not recirculating TCF1 + T cells, predict ovarian cancer outcome. TRM stem cells arise from transitional recirculating T cells, which depends on antigen affinity/persistence, resulting in oligoclonal, trogocytic, effector lymphocytes that eventually become exhausted. Therefore, ovarian cancer is indeed an immunogenic disease, but that depends on ∼13% of CD8 + tumor-infiltrating T cells (∼3% of CD8 + clonotypes), which are primed against high-affinity antigens and maintain waves of effector TRM-like cells. Our results define the signature of relevant tumor-reactive T cells in human ovarian cancer, which could be applicable to other tumors with unideal mutational burden., Competing Interests: Declaration of interests J.R.C.-G. has stock options with Compass Therapeutics, Anixa Biosciences, and Alloy Therapeutics; receives honorarium from Anixa Biosciences, Alloy Therapeutics, and Leidos; and has sponsored research with Anixa Biosciences (all outside the submitted work). B.A.P. has served on the Advisory Board of AstraZeneca and has research support from BMS. J.R.C.-G. is currently an employee of STEMCELL Technologies (all work outside the submitted work). R.M.W. reports grants and personal fees from Merck, personal fees from Tesaro/GSK, personal fees from Genentech, personal fees from Legend Biotech, personal fees from AbbVie, personal fees from Astrazeneca, grants and stock from Ovation Diagnostics, personal fees from Clovis Oncology, and personal fees from Regeneron (all outside the submitted work)., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The immune checkpoint receptor PD-1 on T follicular helper (Tfh) cells promotes Tfh:B cell interactions and appropriate positioning within tissues. Here, we examined the impact of regulation of PD-1 expression by the genomic organizer SATB1 on Tfh cell differentiation. Vaccination of CD4 Cre Satb1 f/f mice enriched for antigen-specific Tfh cells, and TGF-β-mediated repression of SATB1 enhanced Tfh differentiation of human T cells. Mechanistically, high Icos expression in Satb1 -/- CD4 + T cells promoted Tfh cell differentiation by preventing T follicular regulatory cell skewing and resulted in increased isotype-switched B cell responses in vivo. Ovarian tumors in CD4 Cre Satb1 f/f mice accumulated tumor antigen-specific, LIGHT + CXCL13 + IL-21 + Tfh cells and tertiary lymphoid structures (TLS). TLS formation decreased tumor growth in a CD4 + T cell and CXCL13-dependent manner. The transfer of Tfh cells, but not naive CD4 + T cells, induced TLS at tumor beds and decreased tumor growth. Thus, TGF-β-mediated silencing of Satb1 licenses Tfh cell differentiation, providing insight into the genesis of TLS within tumors., Competing Interests: Declaration of interests J.R.C.-G. has stock options with Compass Therapeutics, Anixa Biosciences, and Alloy Therapeutics, receives honorarium from Anixa Biosciences, Alloy Therapeutics, and Leidos, and has sponsored research with Anixa Biosciences. R.L.: Clinical trial protocol committee–CG oncology; Scientific advisor/consultant–B.M.S., Ferring, Fergene, Arquer Diagnostics. B.A.P. has completed Advisory Board with AstraZeneca and has Research Support from B.M.S. J.R. is currently an employee of STEMCELL Technologies., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Precisely how macrophages regulate response to immunotherapy remains unclear. In this issue of Cancer Cell, Chow et al. demonstrate a tumor-promoting role of TIM-4 + cavity macrophages which affects the response of metastatic malignancies to immunotherapy. Specifically, TIM-4 + macrophages engage with phosphatidylserine-expressing cytotoxic T lymphocytes, inhibiting their activity even during PD-1 blockade., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The tumor immune microenvironment (TIME) is a complex ecosystem that contains adaptive and innate immune cells that have tumor-promoting and anti-tumor effects. There is still much to learn about the diversity, plasticity, and functions of innate immune cells in the TIME and their roles in determining the response to immunotherapies. Experts discuss recent advances in our understanding of their biology in cancer as well as outstanding questions and potential therapeutic avenues., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The primary mechanisms supporting immunoregulatory polarization of myeloid cells upon infiltration into tumors remain largely unexplored. Elucidation of these signals could enable better strategies to restore protective anti-tumor immunity. Here, we investigated the role of the intrinsic activation of the PKR-like endoplasmic reticulum (ER) kinase (PERK) in the immunoinhibitory actions of tumor-associated myeloid-derived suppressor cells (tumor-MDSCs). PERK signaling increased in tumor-MDSCs, and its deletion transformed MDSCs into myeloid cells that activated CD8 + T cell-mediated immunity against cancer. Tumor-MDSCs lacking PERK exhibited disrupted NRF2-driven antioxidant capacity and impaired mitochondrial respiratory homeostasis. Moreover, reduced NRF2 signaling in PERK-deficient MDSCs elicited cytosolic mitochondrial DNA elevation and, consequently, STING-dependent expression of anti-tumor type I interferon. Reactivation of NRF2 signaling, conditional deletion of STING, or blockade of type I interferon receptor I restored the immunoinhibitory potential of PERK-ablated MDSCs. Our findings demonstrate the pivotal role of PERK in tumor-MDSC functionality and unveil strategies to reprogram immunosuppressive myelopoiesis in tumors to boost cancer immunotherapy., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

CD103 + dendritic cells are critical for cross-presentation of tumor antigens. Here we have shown that during immunotherapy, large numbers of cells expressing CD103 arose in murine tumors via direct differentiation of Ly6c + monocytic precursors. These Ly6c + CD103 + cells could derive from bone-marrow monocytic progenitors (cMoPs) or from peripheral cells present within the myeloid-derived suppressor cell (MDSC) population. Differentiation was controlled by inflammation-induced activation of the transcription factor p53, which drove upregulation of Batf3 and acquisition of the Ly6c + CD103 + phenotype. Mice with a targeted deletion of p53 in myeloid cells selectively lost the Ly6c + CD103 + population and became unable to respond to multiple forms of immunotherapy and immunogenic chemotherapy. Conversely, increasing p53 expression using a p53-agonist drug caused a sustained increase in Ly6c + CD103 + cells in tumors during immunotherapy, which markedly enhanced the efficacy and duration of response. Thus, p53-driven differentiation of Ly6c + CD103 + monocytic cells represents a potent and previously unrecognized target for immunotherapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)