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The cellular source of positive signals that reinvigorate T cells within the tumor microenvironment (TME) for the therapeutic efficacy of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade has not been clearly defined. We now show that Batf3-lineage dendritic cells (DCs) are essential in this process. Flow cytometric analysis, gene-targeted mice, and blocking antibody studies revealed that 4-1BBL is a major positive co-stimulatory signal provided by these DCs within the TME that translates to CD8 + T cell functional reinvigoration and tumor regression. Immunofluorescence and spatial transcriptomics on human tumor samples revealed clustering of Batf3 + DCs and CD8 + T cells, which correlates with anti-PD-1 efficacy. In addition, proximity to Batf3 + DCs within the TME is associated with CD8 + T cell transcriptional states linked to anti-PD-1 response. Our results demonstrate that Batf3 + DCs within the TME are critical for PD-1/PD-L1 blockade efficacy and indicate a major role for the 4-1BB/4-1BB ligand (4-1BBL) axis during this process., Competing Interests: Declaration of interests T.F.G. has served on scientific advisory boards for Pyxis Oncology, Jounce Therapeutics, Allogene, MAIA, Samyang, Portal Innovations, Fog Pharma, Adaptimmune, Catalym, Bicara, and Merck; is a scientific co-founder and shareholder of Jounce Therapeutics and Pyxis Oncology; and has received research support from Bristol-Myers Squibb, Merck, Pyxis, FogPharma, and Bayer. K.H. is currently working at Merck, and D.E.C.K. is currently working at Slalom., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Over the last decade, the composition of the gut microbiota has been found to correlate with the outcomes of cancer patients treated with immunotherapy. Accumulating evidence points to the various mechanisms by which intestinal bacteria act on distal tumors and how to harness this complex ecosystem to circumvent primary resistance to immune checkpoint inhibitors. Here, we review the state of the microbiota field in the context of melanoma, the recent breakthroughs in defining microbial modes of action, and how to modulate the microbiota to enhance response to cancer immunotherapy. The host-microbe interaction may be deciphered by the use of "omics" technologies, and will guide patient stratification and the development of microbiota-centered interventions. Efforts needed to advance the field and current gaps of knowledge are also discussed., Competing Interests: Declaration of interests B.R. received grand funding from Davolterra and Kanvas and honorarium from Merck, BMS and AstraZeneca. He is also the co-founder of Curebiota. C.K.B. is an employee and stockholder of AbbVie. M.B. sits on the scientific advisory board of Micronoma. A.B. was an employee of Genentech and is a holder of Roche stock. N.C. is CSO of MaaT Pharma. D.D. is a consultant for: ACM Bio, Ascendis Pharma, Clinical Care Options, Gerson Lehrman Group, Merck, Medical Learning Group, Xilio Therapeutics; CE Speakers’ Bureau: Castle Biosciences; and Intellectual Property: US Patent 63/124,231, “Compositions and Methods for Treating Cancer”, Dec 11, 2020 and US Patent 63/208,719, “Compositions and Methods For Responsiveness to Immune Checkpoint Inhibitors (ICI), Increasing Effectiveness of ICI and Treating Cancer”, June 9, 2021. L.D. sits on the scientific advisory board of EverImmune, holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota by LBP, and has been consulting for Ipsen and Sanofi. H.C.H. has filed a patent application (PCT/US2020/019038) for the commercial use of SagA-bacteria to improve checkpoint blockade immunotherapy, which is licensed by Rise Therapeutics to develop immunological-based biologics. M.I. is the founder and shareholder of Bio-Me. G.K. is a consultant for ReiThera; is on the Board of Directors of the Bristol Myers Squibb Foundation France; is a scientific co-founder of EverImmune Ltd., Osasuna Therapeutics, Samsara Therapeutics, and Therafast Bio; and is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis, and metabolic disorders. G.K.’s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. F.M. reports honoraria from Therakos/Mallinckrodt, BMS, Sanofi, Jazz Pharmaceuticals, Gilead, Novartis, and Astellas, all outside the scope of this work. S.P. received travel reimbursement from CRISPR Therapeutics, and Ipsen. Z.R. is the founder of and a Scientific Advisor to Pangea Biomed. B.R. is the co-founder of Curebiota. G.D.S.-P. is an inventor on a US patent application (PCT/US2019/059647) submitted by The Regents of the University of California and licensed by Micronoma that covers methods of diagnosing and treating cancer using multi-domain microbial biomarkers in blood and cancer tissues; a founder of and reports stock interest in Micronoma; and has filed several additional US patent applications on cancer bacteriome and mycobiome diagnostics that are owned by The Regents of the University of California. R.F.S. reports consulting fees from Astellas, AstraZeneca, AVEO, BMS, EMD Serono, Editas, Exelixis, Gilead, Eisai, Janssen, Loxo, Lilly, Mirati, Pfizer, Silverback, and Seattle Genetics; research support (to institution) from Ascendis, ALX Oncology, Astellas, AstraZeneca, Bayer, BMS, CytomX, Eisai, Genentech/Roche, Gilead, Immunocore, Jounce, Loxo, Lilly, Merck, Moderna, Mirati, Novartis, Pfizer, Pionyr, Pyxis, Scholar Rock, QED Therapeutics; equity in AbbVie; and patents: Neoantigens in Cancer, PCT/US2020/031357. M.v.d.B. has received stock options from Seres Therapeutics, Notch Therapeutics, and Pluto Therapeutics; royalties from Wolters Kluwer; consultant for and honorarium from or participated in advisory boards for Seres Therapeutics, Rheos Medicines, Ceramedix, Pluto Therapeutics, Thymofox, Garuda, Novartis (Spouse), Synthekine (Spouse), BeiGene (Spouse), and Kite (Spouse); IP Licensing with Seres Therapeutics and Juno Therapeutics; and holds a fiduciary role on the Foundation Board of DKMS (a nonprofit organization). R.K.W. is a consultant for Takeda Pharmaceuticals. H.Z. sits on the scientific advisory board of EverImmune and is a consultant for MaaT Pharma. L. Zhao is a co-founder of Notitia Biotechnologies Company. J.M. received honoraria from Roche, BMS, and Merck. L. Zitvogel is a co-founder of EverImmune; the President of EverImmune scientific advisory board; holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota by LBP; has held research contracts with bioMérieux, Daiichi Sankyo, Glaxo Smith Kline, Incyte, Lytix, Kaleido, PiLeJe, Transgene, 9 Meters, Tusk Pharma, Merus, Roche, and Innovate Pharma; is on the scientific advisory board of Hookipa; and was on the Board of Directors of Transgene., (Copyright © 2023. Published by Elsevier Inc.)

Agent-based models (ABMs) are a natural platform for capturing the multiple time and spatial scales in biological processes. However, these models are computationally expensive, especially when including molecular-level effects. The traditional approach to simulating this type of multiscale ABM is to solve a system of ordinary differential equations for the molecular events per cell. This significantly adds to the computational cost of simulations as the number of agents grows, which contributes to many ABMs being limited to around 10 5 cells. We propose an approach that requires the same computational time independent of the number of agents. This speeds up the entire simulation by orders of magnitude, allowing for more thorough explorations of ABMs with even larger numbers of agents. We use two systems to show that the new method strongly agrees with the traditionally used approach. This computational strategy can be applied to a wide range of biological investigations., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Understanding the contribution of the host's genetic background to cancer immunity may lead to improved stratification for immunotherapy and to the identification of novel therapeutic targets. We investigated the effect of common and rare germline variants on 139 well-defined immune traits in ∼9000 cancer patients enrolled in TCGA. High heritability was observed for estimates of NK cell and T cell subset infiltration and for interferon signaling. Common variants of IFIH1, TMEM173 (STING1), and TMEM108 were associated with differential interferon signaling and variants mapping to RBL1 correlated with T cell subset abundance. Pathogenic or likely pathogenic variants in BRCA1 and in genes involved in telomere stabilization and Wnt-β-catenin also acted as immune modulators. Our findings provide evidence for the impact of germline genetics on the composition and functional orientation of the tumor immune microenvironment. The curated datasets, variants, and genes identified provide a resource toward further understanding of tumor-immune interactions., Competing Interests: Declarations of interests R.F.S. has received consulting honoraria from Aduro, Astellas, AstraZeneca, BMS, EMD Serono, Exelixis, Eisai, Janssen, Mirati, Pfizer, Puma, and Seattle Genetics. R.F.S. has received research support (to institution) from Abbvie, Aduro, Bayer, BMS, CytomX, Eisai, Eli Lilly, Genentech/Roche, Immunocore, Novartis, Merck, Mirati, Moderna, and QED therapeutics. F.M.M. is an employee of Refuge Biotechnologies. J.G. has patents associated with ‘‘in vitro method for the prognosis of progression of a cancer’’ (PCT/IB2006/003168, PCT/EP2013/062405)” and received royalties from INSERM. J.G. is Co-founder and chairman of the scientific advisory board of HalioDx. J.G. has Collaborative Research Agreement grants with Akoya, IObiotech, MedImmune, AstraZeneca, Janssen, and Imcheck Therapeutics. J.G. participated to Scientific Advisory Boards and is consultant for BMS, Novartis, Merck Serono, IObiotech, Nanostring, Illumina, Northwest Biotherapeutics, Actelion, Amgen, Merck MSD, Lunaphore, Catalym, and Sanofi., (Copyright © 2021 Elsevier Inc. All rights reserved.)