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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.)

Immuno-oncology has traditionally focused on the cellular arm of the adaptive immune response, while attributing tumor-promoting activity to humoral responses in tumor-bearing hosts. This view stems from mouse models that do not necessarily recapitulate the antibody response process consistently observed in most human cancers. In recent years, the field has reconsidered the coordinated action of T and B cell responses in the context of anti-tumor immunity, as in any other immune response. Thus, recent studies in human cancer identify B cell responses with better outcome, typically in association with superior T cell responses. An area of particular interest is tertiary lymphoid structures, where germinal centers produce isotype switched antibodies and B cells and T lymphocytes interact with other immune cell types. The presence of these lymphoid structures is associated with better immunotherapeutic responses and remain poorly understood. Here, we discuss recent discoveries on how coordination between humoral and cellular responses is required for effective immune pressure against malignant progression, providing a perspective on the role of tertiary lymphoid structures and interventions to elicit their formation in unresectable tumors., (Copyright © 2022. Published by Elsevier Ltd.)

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.)

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., Competing Interests: Declaration of interests Y.Z. has received clinical trial support from NewLink Genetics (now Lumos Pharma), which holds the rights to indoximod. S.E. was an employee of ArQule (now a wholly owned subsidiary of Merck & Co., Kenilworth, NJ, USA), which holds the rights to ArQ531. E.K. was an employee of NewLink Genetics (now Lumos Pharma). T.L.M. receives consulting income from FLX Therapeutics. B.R.B. holds intellectual property interests in the therapeutic use of IDO inhibitors; receives remuneration as an advisor to Magenta Therapeutics and BlueRock Therapeutics; and receives research funding from BlueRock Therapeutics, Rheos Medicines, and Equilibre Biopharmaceuticals. T.S.J. has received clinical trial funding from NewLink Genetics (now Lumos Pharma). D.H.M. holds patents and intellectual property interests in the therapeutic use of IDO inhibitors and has received consulting income and research support from NewLink Genetics (now Lumos Pharma). The other authors declare no competing interests., (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.)

Myeloid-derived suppressor cells (MDSCs) impair protective anti-tumor immunity and remain major obstacles that stymie the effectiveness of promising cancer therapies. Diverse tumor-derived stressors galvanize the differentiation, intra-tumoral expansion, and immunomodulatory function of MDSCs. These tumor-associated 'axes of stress' underwrite the immunosuppressive programming of MDSCs in cancer and contribute to the phenotypic/functional heterogeneity that characterize tumor-MDSCs. This review discusses various tumor-associated axes of stress that direct MDSC development, accumulation, and immunosuppressive function, as well as current strategies aimed at overcoming the detrimental impact of MDSCs in cancer. To better understand the constellation of signals directing MDSC biology, we herein summarize the pivotal roles, signaling mediators, and effects of reactive oxygen/nitrogen species-related stress, chronic inflammatory stress, hypoxia-linked stress, endoplasmic reticulum stress, metabolic stress, and therapy-associated stress on MDSCs. Although therapeutic targeting of these processes remains mostly pre-clinical, intercepting signaling through the axes of stress could overcome MDSC-related immune suppression in tumor-bearing hosts., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Regenerative stem cell-like memory (T SCM ) CD8 + T cells persist longer and produce stronger effector functions. We found that MEK1/2 inhibition (MEKi) induces T SCM that have naive phenotype with self-renewability, enhanced multipotency and proliferative capacity. This is achieved by delaying cell division and enhancing mitochondrial biogenesis and fatty acid oxidation, without affecting T cell receptor-mediated activation. DNA methylation profiling revealed that MEKi-induced T SCM cells exhibited plasticity and loci-specific profiles similar to bona fide T SCM isolated from healthy donors, with intermediate characteristics compared to naive and central memory T cells. Ex vivo, antigenic rechallenge of MEKi-treated CD8 + T cells showed stronger recall responses. This strategy generated T cells with higher efficacy for adoptive cell therapy. Moreover, MEKi treatment of tumor-bearing mice also showed strong immune-mediated antitumor effects. In conclusion, we show that MEKi leads to CD8 + T cell reprogramming into T SCM that acts as a reservoir for effector T cells with potent therapeutic characteristics.

Cancer immunotherapy, which stimulates or augments host immune responses to treat malignancies, is the latest development in the rapidly advancing field of cancer immunology. The basic principles of immunotherapies are either to enhance the functions of specific components of the immune system or to neutralize immune-suppressive signals produced by cancer cells or tumor microenvironment cells. When successful, these approaches translate into long-term survival for patients. However, durable responses are only seen in a subset of patients and so far, only in some cancer types. As for other cancer treatments, resistance to immunotherapy can also develop. Numerous research groups are trying to understand why immunotherapy is effective in some patients but not others and to develop strategies to enhance the effectiveness of immunotherapy. The Notch signaling pathway is involved in many aspects of tumor biology, from angiogenesis to cancer stem cell maintenance to tumor immunity. The role of Notch in the development and modulation of the immune response is complex, involving an intricate crosstalk between antigen-presenting cells, T-cell subpopulations, cancer cells, and other components of the tumor microenvironment. Elegant studies have shown that Notch is a central mediator of tumor-induced T-cell anergy and that activation of Notch1 in CD8 T-cells enhances cancer immunotherapy. Tumor-infiltrating myeloid cells, including myeloid-derived suppressor cells, altered dendritic cells, and tumor-associated macrophages along with regulatory T cells, are major obstacles to the development of successful cancer immunotherapies. In this article, we focus on the roles of Notch signaling in modulating tumor-infiltrating myeloid cells and discuss implications for therapeutic strategies that modulate Notch signaling to enhance cancer immunotherapy.

Malignant cells upregulate distinct energy metabolism programs that support their proliferation, migration, and adaptation to the stressful tumor microenvironment (TME). Additionally, this exaggerated metabolic activity allows cancer cells to hijack essential nutrients and outcompete neighboring infiltrating immune cells, thereby impairing antitumor immunity. During recent years, there has been great interest in the field to understand the tumor-induced energy metabolism signals that regulate the function of immune cells in individuals with cancer. Accordingly, it is now well accepted that uncovering the mechanisms that instruct the metabolic behavior of cancer cells and tumor-associated immune cells is an indispensable strategy for the development of new approaches to overcome immune suppression in tumors. Thus, in this minireview, we briefly discuss the interaction between particular metabolic signaling pathways and immunosuppressive activity in different subsets of myeloid cells within the TME. Additionally, we illustrate potential central mechanisms controlling the metabolic reprogramming of myeloid cells in response to tumor-derived factors.

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.)

The endoplasmic reticulum (ER) stress is a cellular process that occurs as a consequence of several stress circumstances, such as the accumulation of unfolded proteins in the lumen of the ER or distinct insults that disturb the ER normal function. Different conditions in the tumor microenvironment (TME), including hypoxia, nutrient deprivation, and the elevated production of reactive oxygen and nitrogen species destabilize the loading and dispatching of the newly synthesized proteins, triggering ER stress in cancer cells and tumor-infiltrating leukocytes. In order to cope with TME-induced ER stress, tumor and stromal cells initiate an adaptive response process that aims to resolve ER stress and to restore cellular homeostasis, which is referred as the unfolded protein responses (UPR). Paradoxically, the UPR can also induce cell death under severe and/or permanent ER stress. The UPR is started through three mediators, the activation of the inositol-requiring enzyme-1α, the pancreatic ER kinase-like ER kinase, and the activating transcription factor 6. In this minireview, we will discuss the pro- and anti-tumorigenic role of the UPR in cancer cells. In addition, we will describe the effects of the TME-induced ER stress in the immunosuppressive activity of tumor-infiltrating myeloid cells. Also, we will review the results of emerging therapeutic interventions that target ER stress and the UPR mediators in cancer. We postulate that the inhibition of ER stress or the UPR-related elements could represent a significant approach to increase the efficacy of various forms of cancer immunotherapy.

The tumor microenvironment is profoundly immunosuppressive. This creates a major barrier for attempts to combine immunotherapy with conventional chemotherapy or radiation, because the tumor antigens released by these cytotoxic agents are not cross-presented in an immunogenic fashion. In this Focused Research Review, we focus on mouse preclinical studies exploring the role of immunosuppressive Tregs expressing the PTEN lipid phosphatase, and the links between PTEN+ Tregs and the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO). IDO has received attention because it can be expressed by a variety of human tumor types in vivo, but IDO can also be induced in host immune cells of both humans and mice in response to inflammation, infection or dying (apoptotic) cells. Mechanistically, IDO and PTEN+ Tregs are closely connected, with IDO causing activation of the PTEN pathway in Tregs. Genetic ablation or pharmacologic inhibition of PTEN in mouse Tregs destabilizes their suppressive phenotype, and this prevents transplantable and autochthonous tumors from creating their normal immunosuppressive microenvironment. Genetic ablation of either IDO or PTEN+ Tregs in mice results in a fundamental defect in the ability to maintain tolerance to antigens associated with apoptotic cells, including dying tumor cells. Consistent with this, pharmacologic inhibitors of either pathway show synergy when combined with cytotoxic agents such as chemotherapy or radiation. Thus, we propose that IDO and PTEN+ Tregs represent closely linked checkpoints that can influence the choice between immune activation versus tolerance to dying tumor cells.

Established tumors build a stressful and hostile microenvironment that blocks the development of protective innate and adaptive immune responses. Different subsets of immunoregulatory myeloid populations, including dendritic cells, myeloid-derived suppressor cells (MDSCs) and macrophages, accumulate in the stressed tumor milieu and represent a major impediment to the success of various forms of cancer immunotherapy. Specific conditions and factors within tumor masses, including hypoxia, nutrient starvation, low pH, and increased levels of free radicals, provoke a state of "endoplasmic reticulum (ER) stress" in both malignant cells and infiltrating myeloid cells. In order to cope with ER stress, cancer cells and tumor-associated myeloid cells activate an integrated signaling pathway known as the Unfolded Protein Response (UPR), which promotes cell survival and adaptation under adverse environmental conditions. However, the UPR can also induce cell death under unresolved levels of ER stress. Three branches of the UPR have been described, including the activation of the inositol-requiring enzyme 1 (IRE1), the pancreatic ER kinase (PKR)-like ER kinase (PERK), and the activating transcription factor 6 (ATF6). In this minireview, we briefly discuss the role of ER stress and specific UPR mediators in tumor development, growth and metastasis. In addition, we describe how sustained ER stress responses operate as key mediators of chronic inflammation and immune suppression within tumors. Finally, we discuss multiple pharmacological approaches that overcome the immunosuppressive effect of the UPR in tumors, and that could potentially enhance the efficacy of cancer immunotherapies by reprogramming the function of tumor-infiltrating myeloid cells.

Myeloid-derived suppressor cells (MDSCs) have emerged as major regulators of immune responses in cancer and other pathological conditions. In recent years, ample evidence supports key contributions of MDSC to tumour progression through both immune-mediated mechanisms and those not directly associated with immune suppression. MDSC are the subject of intensive research with >500 papers published in 2015 alone. However, the phenotypic, morphological and functional heterogeneity of these cells generates confusion in investigation and analysis of their roles in inflammatory responses. The purpose of this communication is to suggest characterization standards in the burgeoning field of MDSC research.

An impaired antitumor immunity is found in patients with cancer and represents a major obstacle in the successful development of different forms of immunotherapy. Signaling through Notch receptors regulates the differentiation and function of many cell types, including immune cells. However, the effect of Notch in CD8(+) T-cell responses in tumors remains unclear. Thus, we aimed to determine the role of Notch signaling in CD8(+) T cells in the induction of tumor-induced suppression. Our results using conditional knockout mice show that Notch-1 and Notch-2 were critical for the proliferation and IFNγ production of activated CD8(+) T cells and were significantly decreased in tumor-infiltrating T cells. Conditional transgenic expression of Notch-1 intracellular domain (N1IC) in antigen-specific CD8(+) T cells did not affect activation or proliferation of CD8(+) T cells, but induced a central memory phenotype and increased cytotoxicity effects and granzyme B levels. Consequently, a higher antitumor response and resistance to tumor-induced tolerance were found after adoptive transfer of N1IC-transgenic CD8(+) T cells into tumor-bearing mice. Additional results showed that myeloid-derived suppressor cells (MDSC) blocked the expression of Notch-1 and Notch-2 in T cells through nitric oxide-dependent mechanisms. Interestingly, N1IC overexpression rendered CD8(+) T cells resistant to the tolerogenic effect induced by MDSC in vivo. Together, the results suggest the key role of Notch in the suppression of CD8(+) T-cell responses in tumors and the therapeutic potential of N1IC in antigen-specific CD8(+) T cells to reverse T-cell suppression and increase the efficacy of T cell-based immunotherapies in cancer., (©2014 American Association for Cancer Research.)

The results from in vitro immunological experiments, murine tumor models and patients with cancer clearly demonstrate that tumors have multiple mechanisms to evade the immune response. During the early stages of tumor development malignant cells can be poor stimulators, present poor targets or become resistant to the innate immune response, while at later stages, progressively growing tumors impair the adaptive immune response by blocking the maturation and function of antigen presenting cells and causing alterations in T cell signal transduction and function. Preliminary results also suggest a correlation between some of these changes and an increased metastatic potential of the tumor cells, a diminished response to immunotherapy, and poor prognosis. Carefully coordinated basic research studies and clinical immunotherapy trials will be required to fully determine the impact on the outcome of the disease and the response to treatment. However, understanding the mechanisms used by tumor cells to evade the immune system could result in new therapeutic approaches for preventing and/or reversing these immune alterations and have the potential of improving the current results of immunotherapy trials.