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Agonistic αCD40 therapy has been shown to inhibit cancer progression in only a fraction of patients. Understanding the cancer cell-intrinsic and microenvironmental determinants of αCD40 therapy response is therefore crucial to identify responsive patient populations and to design efficient combinatorial treatments. Here, we show that the therapeutic efficacy of αCD40 in subcutaneous melanoma relies on preexisting, type 1 classical dendritic cell (cDC1)-primed CD8+ T cells. However, after administration of αCD40, cDC1s were dispensable for antitumor efficacy. Instead, the abundance of activated cDCs, potentially derived from cDC2 cells, increased and further activated antitumor CD8+ T cells. Hence, distinct cDC subsets contributed to the induction of αCD40 responses. In contrast, lung carcinomas, characterized by a high abundance of macrophages, were resistant to αCD40 therapy. Combining αCD40 therapy with macrophage depletion led to tumor growth inhibition only in the presence of strong neoantigens. Accordingly, treatment with immunogenic cell death-inducing chemotherapy sensitized lung tumors to αCD40 therapy in subcutaneous and orthotopic settings. These insights into the microenvironmental regulators of response to αCD40 suggest that different tumor types would benefit from different combinations of therapies to optimize the clinical application of CD40 agonists., Significance: This work highlights the temporal roles of different dendritic cell subsets in promoting CD8+ T-cell-driven responses to CD40 agonist therapy in cancer., (©2022 The Authors; Published by the American Association for Cancer Research.)

IL1β is a central mediator of inflammation. Secretion of IL1β typically requires proteolytic maturation by the inflammasome and formation of membrane pores by gasdermin D (GSDMD). Emerging evidence suggests an important role for IL1β in promoting cancer progression in patients, but the underlying mechanisms are ill-defined. Here, we have shown a key role for IL1β in driving tumor progression in two distinct mouse tumor models. Notably, activation of the inflammasome, caspase-8, as well as the pore-forming proteins GSDMD and mixed lineage kinase domain-like protein in the host were dispensable for the release of intratumoral bioactive IL1β. Inflammasome-independent IL1β release promoted systemic neutrophil expansion and fostered accumulation of T-cell-suppressive neutrophils in the tumor. Moreover, IL1β was essential for neutrophil infiltration triggered by antiangiogenic therapy, thereby contributing to treatment-induced immunosuppression. Deletion of IL1β allowed intratumoral accumulation of CD8 + effector T cells that subsequently activated tumor-associated macrophages. Depletion of either CD8 + T cells or macrophages abolished tumor growth inhibition in IL1β-deficient mice, demonstrating a crucial role for CD8 + T-cell-macrophage cross-talk in the antitumor immune response. Overall, these results support a tumor-promoting role for IL1β through establishing an immunosuppressive microenvironment and show that inflammasome activation is not essential for release of this cytokine in tumors., (©2020 American Association for Cancer Research.)

Over the past decade, cancer immunotherapy has been steering immune responses toward cancer cell eradication. However, these immunotherapeutic approaches are hampered by the tumor-promoting nature of myeloid cells, including monocytes, macrophages, and neutrophils. Despite the arsenal of defense strategies against foreign invaders, myeloid cells succumb to the instructions of an established tumor. Interestingly, the most primordial defense responses employed by myeloid cells against pathogens, such as complement activation, antibody-dependent cell cytotoxicity and phagocytosis, actually seem to favor cancer progression. In this review, we discuss how rudimentary defense mechanisms deployed by myeloid cells can promote tumor progression., (Copyright © 2020 Lebegge, Arnouk, Bardet, Kiss, Raes and Van Ginderachter.)

Excess salt intake could affect the immune system by shifting the immune cell balance toward a pro-inflammatory state. Since this shift of the immune balance is thought to be beneficial in anti-cancer immunity, we tested the impact of high salt diets on tumor growth in mice. Here we show that high salt significantly inhibited tumor growth in two independent murine tumor transplantation models. Although high salt fed tumor-bearing mice showed alterations in T cell populations, the effect seemed to be largely independent of adaptive immune cells. In contrast, depletion of myeloid-derived suppressor cells (MDSCs) significantly reverted the inhibitory effect on tumor growth. In line with this, high salt conditions almost completely blocked murine MDSC function in vitro . Importantly, similar effects were observed in human MDSCs isolated from cancer patients. Thus, high salt conditions seem to inhibit tumor growth by enabling more pronounced anti-tumor immunity through the functional modulation of MDSCs. Our findings might have critical relevance for cancer immunotherapy.

Therapeutic approaches that engage immune cells to treat cancer are becoming increasingly utilized in the clinics and demonstrated durable clinical benefit in several solid tumor types. Most of the current immunotherapies focus on manipulating T cells, however, the tumor microenvironment (TME) is abundantly infiltrated by a heterogeneous population of tumor-associated myeloid cells, including tumor-associated macrophages (TAMs), tumor-associated dendritic cells (TADCs), tumor-associated neutrophils (TANs), and myeloid-derived suppressor cells (MDSCs). Educated by signals perceived in the TME, these cells often acquire tumor-promoting properties ultimately favoring disease progression. Upon appropriate stimuli, myeloid cells can exhibit cytoxic, phagocytic, and antigen-presenting activities thereby bolstering antitumor immune responses. Thus, depletion, reprogramming or reactivation of myeloid cells to either directly eradicate malignant cells or promote antitumor T-cell responses is an emerging field of interest. In this review, we briefly discuss the tumor-promoting and tumor-suppressive roles of myeloid cells in the TME, and describe potential therapeutic strategies in preclinical and clinical development that aim to target them to further expand the range of current treatment options.

Tumors of various histological origins show abundant infiltration of myeloid cells from early stages of disease progression. These cells have a profound impact on antitumor immunity and influence fundamental processes that underlie malignancy, including neoangiogenesis, sustained cancer cell proliferation, metastasis and therapy resistance. For these reasons, development of therapeutic approaches to deplete or reprogram myeloid cells in cancer is an emerging field of interest. However, knowledge about the heterogeneity of myeloid cells in tumors and their variability between patients and disease stages is still limited. In this review, we summarize the most recent advances in our understanding about how the phenotype of tumor-associated macrophages, monocytes, neutrophils, myeloid-derived suppressor cells and dendritic cells is dictated by their ontogeny, activation status and localization. We also outline major open questions that will only be resolved by applying high-dimensional single-cell technologies and systems biology approaches in the analysis of the tumor microenvironment., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Tumor-associated macrophages (TAM) are by now established as important regulators of tumor progression by impacting on tumor immunity, angiogenesis, and metastasis. Hence, a multitude of approaches are currently pursued to intervene with TAM's protumor activities, the most advanced of which being a blockade of macrophage-colony stimulating factor (M-CSF)/M-CSF receptor (M-CSFR) signaling. M-CSFR signaling largely impacts on the differentiation of macrophages, including TAM, and hence strongly influences the numbers of these cells in tumors. However, a repolarization of TAM toward a more antitumor phenotype may be more elegant and may yield stronger effects on tumor growth. In this respect, several aspects of TAM behavior could be altered, such as their intratumoral localization, metabolism and regulatory pathways. Intervention strategies could include the use of small molecules but also new generations of biologicals which may complement the current success of immune checkpoint blockers. This review highlights current work on the search for new therapeutic targets in TAM., (© 2017 Federation of European Biochemical Societies.)

Various steady state and inflamed tissues have been shown to contain a heterogeneous DC population consisting of developmentally distinct subsets, including cDC1s, cDC2s and monocyte-derived DCs, displaying differential functional specializations. The identification of functionally distinct tumour-associated DC (TADC) subpopulations could prove essential for the understanding of basic TADC biology and for envisaging targeted immunotherapies. We demonstrate that multiple mouse tumours as well as human tumours harbour ontogenically discrete TADC subsets. Monocyte-derived TADCs are prominent in tumour antigen uptake, but lack strong T-cell stimulatory capacity due to NO-mediated immunosuppression. Pre-cDC-derived TADCs have lymph node migratory potential, whereby cDC1s efficiently activate CD8 + T cells and cDC2s induce Th17 cells. Mice vaccinated with cDC2s displayed a reduced tumour growth accompanied by a reprogramming of pro-tumoural TAMs and a reduction of MDSCs, while cDC1 vaccination strongly induces anti-tumour CTLs. Our data might prove important for therapeutic interventions targeted at specific TADC subsets or their precursors.

The purpose of this quasi-experimental (pre and posttest) study was to test a model pain management program (PMP) to implement the American Pain Society (APS) quality assurance standards for the management of acute and chronic cancer pain using a continuous quality improvement (CQI) approach to improve professionals' knowledge and skills, patient satisfaction, and to identify areas needing improvement. The sample consisted of 1210 nurse responses and 698 interviews of patients with pain during hospitalization at a major urban cancer center. The PMP provided a structure (standards), educational opportunities, and training in CQI methods. Outcome measures included a patient evaluation questionnaire and concerns checklist; nurse knowledge, attitude and barriers questionnaire; and focus groups to identify areas needing improvement. Significant improvements were found in patients' satisfaction, nurses' knowledge and attitude scores, and reductions in nurses' perceptions of barriers. Focus groups revealed the need for improved communication among disciplines about pain and better assessment of patients unable to self-report. The program met its goal of implementing the APS standards, educating nurses, and identifying "system" problems, and improving overall patient satisfaction.

A stratified, random-assignment trial of 442 cancer patients was conducted to evaluate medical, psychosocial, and financial outcomes of day hospital treatment as an alternative to inpatient care for certain cancer patients. Eligible patients required: a 4- to 8-hour treatment plan, including chemotherapy and other long-term intravenous (i.v.) treatment; a stable cardiovascular status; mental competence; no skilled overnight nursing; and a helper to assist with home care. Patients were ineligible if standard outpatient treatment was possible. No statistically significant (p less than 0.05) differences were found between the Adult Day Hospital (ADH) and Inpatient care in medical or psychosocial outcomes over the 60-day study period. The major difference was in medical costs--approximately one-third lower for ADH patients (p less than 0.001) than for the Inpatient group. The study demonstrates that day hospital care of medical oncology patients is clinically equivalent to Inpatient care, causes no negative psychosocial effects, and costs less than Inpatient care. Findings support the trend toward dehospitalization of medical treatment.