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Despite the remarkable success of anti-cancer immunotherapy, its effectiveness remains confined to a subset of patients-emphasizing the importance of predictive biomarkers in clinical decision-making and further mechanistic understanding of treatment response. Current biomarkers, however, lack the power required to accurately stratify patients. Here, we identify interferon-stimulated, Ly6E hi neutrophils as a blood-borne biomarker of anti-PD1 response in mice at baseline. Ly6E hi neutrophils are induced by tumor-intrinsic activation of the STING (stimulator of interferon genes) signaling pathway and possess the ability to directly sensitize otherwise non-responsive tumors to anti-PD1 therapy, in part through IL12b-dependent activation of cytotoxic T cells. By translating our pre-clinical findings to a cohort of patients with non-small cell lung cancer and melanoma (n = 109), and to public data (n = 1440), we demonstrate the ability of Ly6E hi neutrophils to predict immunotherapy response in humans with high accuracy (average AUC ≈ 0.9). Overall, our study identifies a functionally active biomarker for use in both mice and humans., Competing Interests: Declaration of interests M.B., T.J.C., and Y.S. declare that they hold a pending patent on the use of Ly6E(hi) neutrophils as a predictive biomarker for immunotherapy. P.C. serves on the advisory board to AstraZeneca, Boehringer Ingelheim, Chugai, Pfizer, Novartis, MSD, Takeda and Roche; receives research funds from AstraZeneca, Amgen, Boehringer Ingelheim, Novartis, Roche, and Takeda, receives speaker honoraria from AstraZeneca, Janssen, Novartis, Roche, Pfizer, Thermo Fisher, Takeda. J.B. serves as a consultant to AbbVie, Amgen, AstraZeneca, Bayer, MSD, Merck-Serono, Roche, Takeda, BMS, Medison, Pfizer, and received research funds from Immunai, OncoHost. M.S. holds equity in Actym, Adaptive Biotechnologies, Amphivena, Asher, Evolveimmune, Intensity, Nextcure, Normunity, Oncohost, Johnson and Johnson, Glaxo-Smith Kline; serves as a consultant to Adagene, Adaptimmune, Agenus, Alkermes, Alligator, Anaptys, Asher, Astra Zeneca, Biond, Biontech, Boston Pharmaceuticals, Bristol-Myers, Dragonfly, Evaxion, Evolveimmune, Genentech-Roche, Gilead, Glaxo Smith Kline, Ichnos, Idera, Immunocore, Incyte, Innate pharma, Iovance, iTEOS, Jazz Pharmaceuticals, Kadmon-Sanofi, Kanaph, Merck, Molecular Partners, Nextcure, Nimbus, Normunity, Numab, Ocellaris-Lilly, Oncohost, Ontario Institute for Cancer Research, Partner Therapeutics, Pfizer, Pierre-Fabre, PIO Therapeutics, Pliant, Regeneron, Rootpath, Rubius, Sapience, Simcha, Stcube, Sumitomo, Targovax, Teva, Turnstone, Verastem, Xilio. S.S.O. holds equity in CytoReason and serves as a consultant. Y.S. is a co-founder of OncoHost and RemedyCell, holds equity in these company and also serves as a consultant to both companies., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Chemotherapy remains one of the main treatment modalities for cancer. While chemotherapy is mainly known for its ability to kill tumor cells directly, accumulating evidence indicates that it also acts indirectly by enhancing T cell-mediated anti-tumor immunity sometimes through immunogenic cell death. However, the role of immature immune cells in chemotherapy-induced immunomodulation has not been studied. Here, we utilized a mouse pancreatic cancer model to characterize the effects of gemcitabine chemotherapy on immature bone marrow cells in the context of tumor immunogenicity. Single cell RNA sequencing of hematopoietic stem and progenitor cells revealed a 3-fold increase in megakaryocyte-erythroid progenitors (MEPs) in the bone marrow of gemcitabine-treated mice in comparison to untreated control mice. Notably, adoptive transfer of MEPs to pancreatic tumor-bearing mice significantly reduced tumor growth and increased the levels of anti-tumor immune cells in tumors and peripheral blood. Furthermore, MEPs increased the tumor cell killing activity of CD8 + T cells and NK cells, an effect that was dependent on MEP-secreted CCL5 and CXCL16. Collectively, our findings demonstrate that chemotherapy-induced enrichment of MEPs in the bone marrow compartment contributes to anti-tumor immunity., (© 2023. The Author(s).)

Myeloid-derived suppressor cells (MDSCs) are known to promote tumor growth in part by their immunosuppressive activities and their angiogenesis support. It has been shown that Bv8 blockade inhibits the recruitment of MDSCs to tumors, thereby delaying tumor relapse associated with resistance to antiangiogenic therapy. However, the impact of Bv8 blockade on tumors resistant to the new immunotherapy drugs based on the blockade of immune checkpoints has not been investigated. Here, we demonstrate that granulocytic-MDSCs (G-MDSCs) are enriched in anti-PD1 resistant tumors. Importantly, resistance to anti-PD1 monotherapy is reversed upon switching to a combined regimen comprised of anti-Bv8 and anti-PD1 antibodies. This effect is associated with a decreased level of G-MDSCs and enrichment of active cytotoxic T cells in tumors. The blockade of anti-Bv8 has shown efficacy also in hyperprogressive phenotype of anti-PD1-treated tumors. In vitro , anti-Bv8 antibodies directly inhibit MDSC-mediated immunosuppression, as evidenced by enhanced tumor cell killing activity of cytotoxic T cells. Lastly, we show that anti-Bv8-treated MDSCs secrete proteins associated with effector immune cell function and T cell activity. Overall, we demonstrate that Bv8 blockade inhibits the immunosuppressive function of MDSCs, thereby enhancing anti-tumor activity of cytotoxic T cells and sensitizing anti-PD1 resistant tumors. Our findings suggest that combining Bv8 blockade with anti-PD1 therapy can be used as a strategy for overcoming therapy resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Benguigui, Vorontsova, Timaner, Levin, Haj-Shomaly, Deo, Menachem, Manobla, Cooper, Raviv and Shaked.)

While immense strides have been made in understanding tumor biology and in developing effective treatments that have substantially improved the prognosis of cancer patients, metastasis remains the major cause of cancer-related death. Improvements in the detection and treatment of primary tumors are contributing to a growing, detailed understanding of the dynamics of metastatic progression. Yet challenges remain in detecting metastatic dissemination prior to the establishment of overt metastases and in predicting which patients are at the highest risk of developing metastatic disease. Further improvements in understanding the mechanisms governing metastasis have great potential to inform the adaptation of existing therapies and the development of novel approaches to more effectively control metastatic disease. This article presents a forward-looking perspective on the challenges that remain in the treatment of metastasis, and the exciting emerging approaches that promise to transform the treatment of metastasis in cancer patients., (© 2022. The Author(s).)

Background: The risk of cancer patients to develop COVID19 infection is unclear. We aimed to prospectively study cancer patients and oncology healthcare workers for COVID19 serology. In IgG+ cases, immune profile was determined to portray the pattern of immune response to SARS-CoV2. Methods: Cancer patients on active treatment and healthcare workers were enrolled. During the study period (3/2020-6/2020), demographic data and blood were collected at three time points. Expression of IgG, IgM, and IgA were assessed. In SARS-CoV-2 IgG+ cases and matched negative cases, we performed mass cytometry time of flight (CyTOF) analysis on the basis of the expression of surface markers. Results: The study included 164 cancer patients on active intravenous treatment and 107 healthcare workers at the cancer center. No symptomatic cases were reported during the study period. Serology analysis revealed four IgG+ patients (2.4%) and two IgG+ healthcare workers (1.9%)-all were asymptomatic. CyTOF analysis demonstrated substantial reduction in myeloid cells in healthcare workers who were SARS-CoV-2 IgG+ compared to those who were SARS-CoV-2 IgG-, whereas in cancer patients, the reduction was relatively milder (≈50% reduction in SARS-CoV-2 IgG+ cancer patients compared with ≈90% reduction in SARS-CoV-2 IgG+ workers). Conclusion: Our results indicate a similar rate of asymptomatic COVID19 infection in cancer patients and healthcare workers in a longitudinal study throughout the pandemic time. Due to differential immune cell profiles of cancer patients who are treated with immunomodulatory agents, the host response to the SARS-COV2 may play a role in COVID19 course and representation. The immunological perspective of cancer treatments on the risk for COVID19 infection should be further explored.

The impressive successes of immune checkpoint blockade antibodies to treat various types of cancer are limited to minor subsets of patients. Combination therapy strategies, including with chemotherapy, are being explored to possibly improve the efficacy of immunotherapies. Here we report results regarding the use of an immunostimulatory regimen of metronomic cyclophosphamide (CTX). We show that in orthotopic models of syngeneic murine triple-negative breast cancer (EMT6), CTX administered at 140 mg/kg every 6 days (CTX140 1q6d) is superior at inhibiting primary tumor growth when compared to maximum tolerated dose or daily oral (continuous) low-dose CTX. In SCID or SCID beige mice, anti-tumor effects of CTX140 1q6d are reduced, reinforcing the therapeutic contribution of the adaptive and innate immune systems. In a second breast cancer model (SP1-AC2M2), CTX140 1q6d again showed clear superiority in anti-tumor effects, causing complete tumor regressions; however, these mice were not protected from subsequent tumor re-challenge, suggesting absence of immune memory. We also show that in an aggressive and metastatic cisplatin-resistant variant (EMT6-CDDP), CTX140 1q6d is superior and invokes an influx of intra-tumoral CD4 + and CD8 + T cells. CTX increases expression of tumor cell PD-L1; however, when combined with concomitant PD-L1 antibody therapy none of the CTX regimens showed increased benefit. This work sheds light on the potential use of metronomic CTX for the treatment of breast cancer, in particular using the quasi-weekly regimen, but also underscores the complexity of the anti-tumor mechanisms and potential to improve immune checkpoint therapy efficacy., Competing Interests: Competing interestsR.S.K. is a member of the Scientific Advisory Boards and consultant of CSTS Healthcare (Toronto, Canada) and NED Biosystems (Boston, USA) and a recipient of a sponsored research agreement with Genentech (San Francisco, USA). All other authors declare no conflict of interest., (© The Author(s) 2020.)

Cancer stem cells, also termed tumor initiating cells (TICs), are a rare population of cells within the tumor mass which initiate tumor growth and metastasis. In pancreatic cancer, TICs significantly contribute to tumor re-growth after therapy, due to their intrinsic resistance. Here we demonstrate that copper oxide nanoparticles (CuO-NPs) are cytotoxic against TIC-enriched PANC1 human pancreatic cancer cell cultures. Specifically, treatment with CuO-NPs decreases cell viability and increases apoptosis in TIC-enriched PANC1 cultures to a greater extent than in standard PANC1 cultures. These effects are associated with increased reactive oxygen species (ROS) levels, and reduced mitochondrial membrane potential. Furthermore, we demonstrate that CuO-NPs inhibit tumor growth in a pancreatic tumor model in mice. Tumors from mice treated with CuO-NPs contain a significantly higher number of apoptotic TICs in comparison to tumors from untreated mice, confirming that CuO-NPs target TICs in vivo. Overall, our findings highlight the potential of using CuO-NPs as a new therapeutic modality for pancreatic cancer.

European genetic gradients of modern humans were initially interpreted as a consequence of the demic diffusion of expanding Neolithic farmers. However, recent studies showed that these gradients may also be influenced by other evolutionary processes such as population admixture or range contractions. Genetic gradients were observed in the Americas, although their specific evolutionary causes were not investigated. Here we extended the approach used to study genetic gradients in Europe to analyze the influence of diverse evolutionary scenarios on American genetic gradients. Using extensive computer simulations, we evaluated the impact of (i) admixture between expansion waves of modern humans, (ii) the presence of ice-sheets during the last glacial maximum (LGM) and (iii) long-distance dispersal (LDD) events, on the genetic gradients (detected by principal component analysis) of the entire continent, North America and South America. The specific simulation of North and South America showed that genetic gradients are usually orthogonal to the direction of range expansions-either expansions from Bering or posterior re-expansions to recolonize northern regions after ice sheets melting-and we suggest that they result from allele surfing processes. Conversely, our results on the entire continent show a northwest-southeast gradient obtained with any scenario, which we interpreted as a consequence of isolation by distance along the long length of the continent. These findings suggest that distinct genetic gradients can be detected at different regions of the Americas and that subcontinent regions present gradients more sensible to evolutionary and environmental factors (such as LDD and the LGM) than the whole continent.

Copper oxide nanoparticles (CuO-NPs) are increasingly becoming the subject of investigation exploring their potential use for diagnostic and therapeutic purposes. Recent work has demonstrated their anticancer potential, as well as contrast agent capabilities for magnetic resonance imaging (MRI) and through-transmission ultrasound. However, no capability of CuO-NPs has been demonstrated using conventional ultrasound systems, which, unlike the former, are widely deployed in the clinic. Furthermore, in spite of their potential as multifunctional nano-based materials for diagnosis and therapy, CuO-NPs have been delayed from further clinical application due to their inherent toxicity. Herein, we present the synthesis of a novel nanoscale system, composed of CuO-loaded PLGA nanospheres (CuO-PLGA-NS), and demonstrate its imaging detectability and augmented heating effect by therapeutic ultrasound. The CuO-PLGA-NS were prepared by a double emulsion (W/O/W) method with subsequent solvent evaporation. They were characterized as sphere-shaped, with size approximately 200 nm. Preliminary results showed that the viability of PANC-1, human pancreatic adenocarcinoma cells was not affected after 72 h exposure to CuO-PLGA-NS, implying that PLGA masks the toxic effects of CuO-NPs. A systematic ultrasound imaging evaluation of CuO-PLGA-NS, using a conventional system, was performed in vitro and ex vivo using poultry heart and liver, and also in vivo using mice, all yielding a significant contrast enhancement. In contrast to CuO-PLGA-NS, neither bare CuO-NPs nor blank PLGA-NS possess these unique advantageous ultrasonic properties. Furthermore, CuO-PLGA-NS accelerated ultrasound-induced temperature elevation by more than 4 °C within 2 min. The heating efficiency (cumulative equivalent minutes at 43 °C) was increased approximately six-fold, demonstrating the potential for improved ultrasound ablation. In conclusion, CuO-PLGA-NS constitute a versatile platform, potentially useful for combined imaging and therapeutic ultrasound-based procedures.

Stromal cells residing in the tumor microenvironment contribute to the development of therapy resistance. Here we show that chemotherapy-educated mesenchymal stem cells (MSC) promote therapy resistance via cross-talk with tumor-initiating cells (TIC), a resistant tumor cell subset that initiates tumorigenesis and metastasis. In response to gemcitabine chemotherapy, MSCs colonized pancreatic adenocarcinomas in large numbers and resided in close proximity to TICs. Furthermore, gemcitabine-educated MSCs promoted the enrichment of TICs in vitro and enhance tumor growth in vivo These effects were dependent on the secretion of CXCL10 by gemcitabine-educated MSCs and subsequent activation of the CXCL10-CXCR3 axis in TICs. In an orthotopic pancreatic tumor model, targeting TICs using nanovesicles (called nanoghosts) derived from MSC membranes and loaded with a CXCR3 antagonist enhanced therapy outcome and delayed tumor regrowth when administered in combination with gemcitabine. Overall, our results establish a mechanism through which MSCs promote chemoresistance, and propose a novel drug delivery system to target TICs and overcome this resistance. Significance: These results establish a mechanism by which mesenchyme stem cells in the tumor microenvironment promote chemoresistance, and they propose a novel drug delivery system to overcome this challenge. Cancer Res; 78(5); 1253-65. ©2018 AACR ., (©2018 American Association for Cancer Research.)

It has recently been suggested that pro-tumorigenic host-mediated processes induced in response to chemotherapy counteract the anti-tumor activity of therapy, and thereby decrease net therapeutic outcome. Here we use experimental data to formulate a mathematical model describing the host response to different doses of paclitaxel (PTX) chemotherapy as well as the duration of the response. Three previously described host-mediated effects are used as readouts for the host response to therapy. These include the levels of circulating endothelial progenitor cells in peripheral blood and the effect of plasma derived from PTX-treated mice on migratory and invasive properties of tumor cells in vitro . A first set of mathematical models, based on basic principles of pharmacokinetics/pharmacodynamics, did not appropriately describe the dose-dependence and duration of the host response regarding the effects on invasion. We therefore provide an alternative mathematical model with a dose-dependent threshold, instead of a concentration-dependent one, that describes better the data. This model is integrated into a global model defining all three host-mediated effects. It not only precisely describes the data, but also correctly predicts host-mediated effects at different doses as well as the duration of the host response. This mathematical model may serve as a tool to predict the host response to chemotherapy in cancer patients, and therefore may be used to design chemotherapy regimens with improved therapeutic outcome by minimizing host mediated effects., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Analyses of human evolution are fundamental to understand the current gradients of human diversity. In this concern, genetic samples collected from current populations together with archaeological data are the most important resources to study human evolution. However, they are often insufficient to properly evaluate a variety of evolutionary scenarios, leading to continuous debates and discussions. A commonly applied strategy consists of the use of computer simulations based on, as realistic as possible, evolutionary models, to evaluate alternative evolutionary scenarios through statistical correlations with the real data. Computer simulations can also be applied to estimate evolutionary parameters or to study the role of each parameter on the evolutionary process. Here we review the mainly used methods and evolutionary frameworks to perform realistic spatially explicit computer simulations of human evolution. Although we focus on human evolution, most of the methods and software we describe can also be used to study other species. We also describe the importance of considering spatially explicit models to better mimic human evolutionary scenarios based on a variety of phenomena such as range expansions, range shifts, range contractions, sex-biased dispersal, long-distance dispersal or admixtures of populations. We finally discuss future implementations to improve current spatially explicit simulations and their derived applications in human evolution.