Neoantigen-specific stimulation of tumor-infiltrating lymphocytes enables effective TCR isolation and expansion while preserving stem-like memory phenotypes.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) targeting neoantigens can effectively treat a selected set of metastatic solid cancers. However, harnessing TILs for cancer treatments remains challenging because neoantigen-reactive T cells are often rare and exhausted, and ex vivo expansion can further reduce their frequencies. This complicates the identification of neoantigen-reactive T-cell receptors (TCRs) and the development of TIL products with high reactivity for patient treatment. METHODS: We tested whether TILs could be in vitro stimulated against neoantigens to achieve selective expansion of neoantigen-reactive TILs. Given their prevalence, mutant p53 or RAS were studied as models of human neoantigens. An in vitro stimulation method, termed "NeoExpand", was developed to provide neoantigen-specific stimulation to TILs. 25 consecutive patient TILs from tumors harboring p53 or RAS mutations were subjected to NeoExpand. RESULTS: We show that neoantigenic stimulation achieved selective expansion of neoantigen-reactive TILs and broadened the neoantigen-reactive CD4+ and CD8+ TIL clonal repertoire. This allowed the effective isolation of novel neoantigen-reactive TCRs. Out of the 25 consecutive TIL samples, neoantigenic stimulation enabled the identification of 16 unique reactivities and 42 TCRs, while conventional TIL expansion identified 9 reactivities and 14 TCRs. Single-cell transcriptome analysis revealed that neoantigenic stimulation increased neoantigen-reactive TILs with stem-like memory phenotypes expressing IL-7R, CD62L, and KLF2. Furthermore, neoantigenic stimulation improved the in vivo antitumor efficacy of TILs relative to the conventional OKT3-induced rapid TIL expansion in p53-mutated or KRAS-mutated xenograft mouse models. CONCLUSIONS: Taken together, neoantigenic stimulation of TILs selectively expands neoantigen-reactive TILs by frequencies and by their clonal repertoire. NeoExpand led to improved phenotypes and functions of neoantigen-reactive TILs. Our data warrant its clinical evaluation. TRIAL REGISTRATION NUMBER: NCT00068003, NCT01174121, and NCT03412877.

Phenotypic signatures of circulating neoantigen-reactive CD8+ T cells in patients with metastatic cancers.

Circulating T cells from peripheral blood (PBL) can provide a rich and noninvasive source for antitumor T cells. By single-cell transcriptomic profiling of 36 neoantigen-specific T cell clones from 6 metastatic cancer patients, we report the transcriptional and cell surface signatures of antitumor PBL-derived CD8+ T cells (NeoTCRPBL). Comparison of tumor-infiltrating lymphocyte (TIL)- and PBL-neoantigen-specific T cells revealed that NeoTCRPBL T cells are low in frequency and display less-dysfunctional memory phenotypes relative to their TIL counterparts. Analysis of 100 antitumor TCR clonotypes indicates that most NeoTCRPBL populations target the same neoantigens as TILs. However, NeoTCRPBL TCR repertoire is only partially shared with TIL. Prediction and testing of NeoTCRPBL signature-derived TCRs from PBL of 6 prospective patients demonstrate high enrichment of clonotypes targeting tumor mutations, a viral oncogene, and patient-derived tumor. Thus, the NeoTCRPBL signature provides an alternative source for identifying antitumor T cells from PBL of cancer patients, enabling immune monitoring and immunotherapies.

Quantifying the Variability of Ground Light Sources and Their Relationships with Spaceborne Observations of Night Lights Using Multidirectional and Multispectral Measurements.

With the transition to LED lighting technology, multispectral night-time sensors are needed to quantify the changing nightscapes, given the limitations of the panchromatic sensors. Our objective was to quantify the contribution of lighting sources as measured on the ground and examine their correspondence with night-time brightness and color as measured from space. We conducted ground-based measurements of night-time brightness using the multidirectional (top, rear, right, front, left) and multispectral LANcube v2, which was mounted on the roof of a car, over 458 km of roads in central Israel and in Brisbane, Australia. For spaceborne measurements, we used the SDGSAT-1 multispectral Glimmer sensor. We found that spaceborne measurements of apparent radiance were best explained when including all ground-based directional measurements, with greater explanatory power for highways (R2 = 0.725) than for urban roads (R2 = 0.556). Incoming light in the five directions varied between road classes and land use. In most cases, the variability in night-time brightness and color was greater for urban road sections than for highways. We conclude that due to the spectral mixture of lighting sources, at a medium spatial resolution, the impact of the transition to LED lighting may be more easily recognized from space over highways than in dense urban settings.

Adoptive Cellular Therapy with Autologous Tumor-Infiltrating Lymphocytes and T-cell Receptor-Engineered T Cells Targeting Common p53 Neoantigens in Human Solid Tumors.

Adoptive cellular therapy (ACT) targeting neoantigens can achieve durable clinical responses in patients with cancer. Most neoantigens arise from patient-specific mutations, requiring highly individualized treatments. To broaden the applicability of ACT targeting neoantigens, we focused on TP53 mutations commonly shared across different cancer types. We performed whole-exome sequencing on 163 patients with metastatic solid cancers, identified 78 who had TP53 missense mutations, and through immunologic screening, identified 21 unique T-cell reactivities. Here, we report a library of 39 T-cell receptors (TCR) targeting TP53 mutations shared among 7.3% of patients with solid tumors. These TCRs recognized tumor cells in a TP53 mutation- and human leucocyte antigen (HLA)-specific manner in vitro and in vivo. Twelve patients with chemorefractory epithelial cancers were treated with ex vivo-expanded autologous tumor-infiltrating lymphocytes (TIL) that were naturally reactive against TP53 mutations. However, limited clinical responses (2 partial responses among 12 patients) were seen. These infusions contained low frequencies of mutant p53-reactive TILs that had exhausted phenotypes and showed poor persistence. We also treated one patient who had chemorefractory breast cancer with ACT comprising autologous peripheral blood lymphocytes transduced with an allogeneic HLA-A*02-restricted TCR specific for p53R175H. The infused cells exhibited an improved immunophenotype and prolonged persistence compared with TIL ACT and the patient experienced an objective tumor regression (-55%) that lasted 6 months. Collectively, these proof-of-concept data suggest that the library of TCRs targeting shared p53 neoantigens should be further evaluated for the treatment of patients with advanced human cancers. See related Spotlight by Klebanoff, p. 919.

Molecular signatures of antitumor neoantigen-reactive T cells from metastatic human cancers.

The accurate identification of antitumor T cell receptors (TCRs) represents a major challenge for the engineering of cell-based cancer immunotherapies. By mapping 55 neoantigen-specific TCR clonotypes (NeoTCRs) from 10 metastatic human tumors to their single-cell transcriptomes, we identified signatures of CD8+ and CD4+ neoantigen-reactive tumor-infiltrating lymphocytes (TILs). Neoantigen-specific TILs exhibited tumor-specific expansion with dysfunctional phenotypes, distinct from blood-emigrant bystanders and regulatory TILs. Prospective prediction and testing of 73 NeoTCR signature-derived clonotypes demonstrated that half of the tested TCRs recognized tumor antigens or autologous tumors. NeoTCR signatures identified TCRs that target driver neoantigens and nonmutated viral or tumor-associated antigens, suggesting a common metastatic TIL exhaustion program. NeoTCR signatures delineate the landscape of TILs across metastatic tumors, enabling successful TCR prediction based purely on TIL transcriptomic states for use in cancer immunotherapy.

Accelerated shifts in terrestrial life zones under rapid climate change.

Rapid climate change is impacting biodiversity, ecosystem function, and human well-being. Though the magnitude and trajectory of climate change are becoming clearer, our understanding of how these changes reshape terrestrial life zones-distinct biogeographic units characterized by biotemperature, precipitation, and aridity representing broad-scale ecosystem types-is limited. To address this gap, we used high-resolution historical climatologies and climate projections to determine the global distribution of historical (1901-1920), contemporary (1979-2013), and future (2061-2080) life zones. Comparing the historical and contemporary distributions shows that changes from one life zone to another during the 20th century impacted 27 million km2 (18.3% of land), with consequences for social and ecological systems. Such changes took place in all biomes, most notably in Boreal Forests, Temperate Coniferous Forests, and Tropical Coniferous Forests. Comparing the contemporary and future life zone distributions shows the pace of life zone changes accelerating rapidly in the 21st century. By 2070, such changes would impact an additional 62 million km2 (42.6% of land) under "business-as-usual" (RCP8.5) emissions scenarios. Accelerated rates of change are observed in hundreds of ecoregions across all biomes except Tropical Coniferous Forests. While only 30 ecoregions (3.5%) had over half of their areas change to a different life zone during the 20th century, by 2070 this number is projected to climb to 111 ecoregions (13.1%) under RCP4.5 and 281 ecoregions (33.2%) under RCP8.5. We identified weak correlations between life zone change and threatened vertebrate richness, levels of vertebrate endemism, cropland extent, and human population densities within ecoregions, illustrating the ubiquitous risks of life zone changes to diverse social-ecological systems. The accelerated pace of life zone changes will increasingly challenge adaptive conservation and sustainable development strategies that incorrectly assume current ecological patterns and livelihood provisioning systems will persist.

Identification and Validation of T-cell Receptors Targeting RAS Hotspot Mutations in Human Cancers for Use in Cell-based Immunotherapy.

PURPOSE: Immunotherapies mediate the regression of human tumors through recognition of tumor antigens by immune cells that trigger an immune response. Mutations in the RAS oncogenes occur in about 30% of all patients with cancer. These mutations play an important role in both tumor establishment and survival and are commonly found in hotspots. Discovering T-cell receptors (TCR) that recognize shared mutated RAS antigens presented on MHC class I and class II molecules are thus promising reagents for "off-the-shelf" adoptive cell therapies (ACT) following insertion of the TCRs into lymphocytes. EXPERIMENTAL DESIGN: In this ongoing work, we screened for RAS antigen recognition in tumor-infiltrating lymphocytes (TIL) or by in vitro stimulation of peripheral blood lymphocytes (PBL). TCRs recognizing mutated RAS were identified from the reactive T cells. The TCRs were then reconstructed and virally transduced into PBLs and tested. RESULTS: Here, we detect and report multiple novel TCR sequences that recognize nonsynonymous mutant RAS hotspot mutations with high avidity and specificity and identify the specific class-I and -II MHC restriction elements involved in the recognition of mutant RAS. CONCLUSIONS: The TCR library directed against RAS hotspot mutations described here recognize RAS mutations found in about 45% of the Caucasian population and about 60% of the Asian population and represent promising reagents for "off-the-shelf" ACTs.

The Intracellular Domain of CD40 is a Potent Costimulatory Element in Chimeric Antigen Receptors.

The costimulatory domains incorporated into second-generation and third-generation chimeric antigen receptors (CARs) strongly influence CAR-T-cell function. Here, we explored second-generation and third-generation CARs harboring the signaling domain of the CD40 receptor as a new costimulatory element in comparison with similar CARs carrying the 4-1BB domain. In CARs of both generations, CD40 was more potent than 4-1BB in triggering the NF-κB signaling pathway. In human T cells from 2 donors, CD40 was comparable to 4-1BB in upregulating costimulatory and activation markers, inducing proinflammatory cytokine secretion and mediating target cell killing. Interestingly, differences in the response pattern of T cells from the 2 donors with respect to CD40 and 4-1BB were evident. We conclude that in human T cells, the CD40 signaling domain is a potent costimulatory element in both second-generation and third-generation CARs.

Spatial and temporal assessment of oil spills in the Mediterranean Sea.

Ship-generated oil pollution is a significant threat to the Mediterranean Sea. We present a geostatistical analysis of oil spills using three databases for the Mediterranean Sea: REMPEC (1977-2000) with 385 spills (17/year), ITOPF (1970-2018) with 167 spills (3.5/year) and EMSA (2015-2017) with 2066 detections (688/year). It was found that 88% of spills reported by REMPEC occurred near coastline areas, while 65% of the spills detected by EMSA occurred within a range of 22-100 km from the coastline. At the Exclusive Economic Zone (EEZ) level, EMSA oil spills densities were positively correlated with shipping and port activity. We conclude that there is a need to develop an open-access database of oil spills that will be based on both reports and remote sensing acquisition methods. Such a database will facilitate more efficient enforcement of international conventions in offshore areas and will increase the likelihood of effective response.

Rapid Identification and Evaluation of Neoantigen-reactive T-Cell Receptors From Single Cells.

Engineered T cells expressing tumor-specific T-cell receptors (TCRs) are emerging as a mode of personalized cancer immunotherapy that requires identification of TCRs against the products of known driver mutations and novel mutations in a timely fashion. We present a nonviral and non-next-generation sequencing platform for rapid, and efficient neoantigen-specific TCR identification and evaluation that does not require the use of recombinant cloning techniques. The platform includes an innovative method of TCRα detection using Sanger sequencing, TCR pairings and the use of TCRα/ß gene fragments for putative TCR evaluation. Using patients' samples, we validated and compared our new methods head-to-head with conventional approaches used for TCR discovery. Development of a unique demultiplexing method for identification of TCRα, adaptation of synthetic TCRs for gene transfer, and a reliable reporter system significantly shortens TCR discovery time over conventional methods and increases throughput to facilitate testing prospective personalized TCRs for adoptive cell therapy.

mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer.

BACKGROUNDTherapeutic vaccinations against cancer have mainly targeted differentiation antigens, cancer-testis antigens, and overexpressed antigens and have thus far resulted in little clinical benefit. Studies conducted by multiple groups have demonstrated that T cells recognizing neoantigens are present in most cancers and offer a specific and highly immunogenic target for personalized vaccination.METHODSWe recently developed a process using tumor-infiltrating lymphocytes to identify the specific immunogenic mutations expressed in patients' tumors. Here, validated, defined neoantigens, predicted neoepitopes, and mutations of driver genes were concatenated into a single mRNA construct to vaccinate patients with metastatic gastrointestinal cancer.RESULTSThe vaccine was safe and elicited mutation-specific T cell responses against predicted neoepitopes not detected before vaccination. Furthermore, we were able to isolate and verify T cell receptors targeting KRASG12D mutation. We observed no objective clinical responses in the 4 patients treated in this trial.CONCLUSIONThis vaccine was safe, and potential future combination of such vaccines with checkpoint inhibitors or adoptive T cell therapy should be evaluated for possible clinical benefit in patients with common epithelial cancers.TRIAL REGISTRATIONPhase I/II protocol (NCT03480152) was approved by the IRB committee of the NIH and the FDA.FUNDINGCenter for Clinical Research, NCI, NIH.

Preexisting coronary heart disease and susceptibility to long-term effects of traffic-related air pollution: A matched cohort analysis.

BACKGROUND: Individuals with coronary heart disease are considered susceptible to traffic-related air pollution exposure. Yet, cohort-based evidence on whether preexisting coronary heart disease modifies the association of traffic-related air pollution with health outcomes is lacking. AIM: Using data of four Israeli cohorts, we compared associations of traffic-related air pollution with mortality and cancer between coronary heart disease patients and matched controls from the general population. METHODS: Subjects hospitalized with acute coronary syndrome from two patient cohorts (inception years: 1992-1993 and 2006-2014) were age- and sex-matched to coronary heart disease-free participants of two cycles of the Israeli National Health and Nutrition Surveys (inception years: 1999-2001 and 2005-2006). Ambient concentrations of nitrogen oxides at the residential place served as a proxy for traffic-related air pollution exposure across all cohorts, based on a high-resolution national land use regression model (50 m). Data on all-cause mortality (last update: 2018) and cancer incidence (last update: 2016) were retrieved from national registries. Cox-derived stratum-specific hazard ratios with 95% confidence intervals were calculated, adjusted for harmonized covariates across cohorts, including age, sex, ethnicity, neighborhood socioeconomic status, smoking, diabetes, hypertension, prior stroke and prior malignancy (the latter only in the mortality analysis). Effect-modification was examined by testing nitrogen oxides-by-coronary heart disease interaction term in the entire matched cohort. RESULTS: The cohort (mean (standard deviation) age 61.5 (14) years; 44% women) included 2393 matched pairs, among them 2040 were cancer-free at baseline. During a median (25th-75th percentiles) follow-up of 13 (10-19) and 11 (7-17) years, 1458 deaths and 536 new cancer cases were identified, respectively. In multivariable-adjusted models, a 10-parts per billion nitrogen oxides increment was positively associated with all-cause mortality among coronary heart disease patients (hazard ratio = 1.13, 95% confidence interval 1.05-1.22), but not among controls (hazard ratio = 1.00, 0.93-1.08) (pinteraction = 0.003). A similar pattern was seen for all-cancer incidence (hazard ratioCHD = 1.19 (1.03-1.37), hazard ratioCHD-Free = 0.93 (0.84-1.04) (pinteraction = 0.01)). Associations were robust to multiple sensitivity analyses. CONCLUSIONS: Coronary heart disease patients might be at increased risk for traffic-related air pollution-associated mortality and cancer, irrespective of their age and sex. Patients and clinicians should be more aware of the adverse health effects on coronary heart disease patients of chronic exposure to vehicle emissions.

Ecological variables for developing a global deep-ocean monitoring and conservation strategy.

The deep sea (>200 m depth) encompasses >95% of the world's ocean volume and represents the largest and least explored biome on Earth (<0.0001% of ocean surface), yet is increasingly under threat from multiple direct and indirect anthropogenic pressures. Our ability to preserve both benthic and pelagic deep-sea ecosystems depends upon effective ecosystem-based management strategies and monitoring based on widely agreed deep-sea ecological variables. Here, we identify a set of deep-sea essential ecological variables among five scientific areas of the deep ocean: (1) biodiversity; (2) ecosystem functions; (3) impacts and risk assessment; (4) climate change, adaptation and evolution; and (5) ecosystem conservation. Conducting an expert elicitation (1,155 deep-sea scientists consulted and 112 respondents), our analysis indicates a wide consensus amongst deep-sea experts that monitoring should prioritize large organisms (that is, macro- and megafauna) living in deep waters and in benthic habitats, whereas monitoring of ecosystem functioning should focus on trophic structure and biomass production. Habitat degradation and recovery rates are identified as crucial features for monitoring deep-sea ecosystem health, while global climate change will likely shift bathymetric distributions and cause local extinction in deep-sea species. Finally, deep-sea conservation efforts should focus primarily on vulnerable marine ecosystems and habitat-forming species. Deep-sea observation efforts that prioritize these variables will help to support the implementation of effective management strategies on a global scale.

Cancer and mortality in relation to traffic-related air pollution among coronary patients: Using an ensemble of exposure estimates to identify high-risk individuals.

BACKGROUND: Moderate correlations were previously observed between individual estimates of traffic-related air pollution (TRAP) produced by different exposure modeling approaches. This induces exposure misclassification for a substantial fraction of subjects. AIM: We used an ensemble of well-established modeling approaches to increase certainty of exposure classification and reevaluated the association with cancers previously linked to TRAP (lung, breast and prostate), other cancers, and all-cause mortality in a cohort of coronary patients. METHODS: Patients undergoing percutaneous coronary interventions in a major Israeli medical center from 2004 to 2014 (n = 10,627) were followed for cancer (through 2015) and mortality (through 2017) via national registries. Residential exposure to nitrogen oxides (NOx) -a proxy for TRAP- was estimated by optimized dispersion model (ODM) and land use regression (LUR) (rPearson = 0.50). Mutually exclusive groups of subjects classified as exposed by none of the methods (high-certainty low-exposed), ODM alone, LUR alone, or both methods (high-certainty high-exposed) were created. Associations were examined using Cox regression models. RESULTS: During follow-up, 741 incident cancer cases were diagnosed and 3051 deaths occurred. Using a ≥25 ppb cutoff, compared with high-certainty low exposed, the multivariable-adjusted hazard ratios (95% confidence intervals) for lung, breast and prostate cancer were 1.56 (1.13-2.15) in high-certainty exposed, 1.27 (0.86-1.86) in LUR-exposed alone, and 1.13 (0.77-1.65) in ODM-exposed alone. The association of the former category was strengthened using more extreme NOx cutoffs. A similar pattern, albeit less strong, was observed for mortality, whereas no association was shown for cancers not previously linked to TRAP. CONCLUSIONS: Use of an ensemble of TRAP exposure estimates may improve classification, resulting in a stronger association with outcomes.

Global assessment of marine biodiversity potentially threatened by offshore hydrocarbon activities.

Increasing global energy demands have led to the ongoing intensification of hydrocarbon extraction from marine areas. Hydrocarbon extractive activities pose threats to native marine biodiversity, such as noise, light, and chemical pollution, physical changes to the sea floor, invasive species, and greenhouse gas emissions. Here, we assessed at a global scale the spatial overlap between offshore hydrocarbon activities and marine biodiversity (>25,000 species, nine major ecosystems, and marine protected areas), and quantify the changes over time. We discovered that two-thirds of global offshore hydrocarbon activities occur in areas within the top 10% for species richness, range rarity, and proportional range rarity values globally. Thus, while hydrocarbon activities are undertaken in less than one percent of the ocean's area, they overlap with approximately 85% of all assessed species. Of conservation concern, 4% of species with the largest proportion of their range overlapping hydrocarbon activities are range restricted, potentially increasing their vulnerability to localized threats such as oil spills. While hydrocarbon activities have extended to greater depths since the mid-1990s, we found that the largest overlap is with coastal ecosystems, particularly estuaries, saltmarshes and mangroves. Furthermore, in most countries where offshore hydrocarbon exploration licensing blocks have been delineated, they do not overlap with marine protected areas (MPAs). Although this is positive in principle, many countries have far more licensing block areas than protected areas, and in some instances, MPA coverage is minimal. These findings suggest the need for marine spatial prioritization to help limit future spatial overlap between marine conservation priorities and hydrocarbon activities. Such prioritization can be informed by the spatial and quantitative baseline information provided here. In increasingly shared seascapes, prioritizing management actions that set both conservation and development targets could help minimize further declines of biodiversity and environmental changes at a global scale.

Combined Expression of Genetic Adjuvants Via mRNA Electroporation Exerts Multiple Immunostimulatory Effects on Antitumor T Cells.

Adoptive transfer of tumor-infiltrating lymphocytes (TILs) or gene-modified T cells expressing antitumor TCRs or chimeric antigen receptors often yields a high rate of clinical response in several types of cancer. New approaches for enhancing the functional properties of antitumor T cells could improve the clinical outcome of these treatments. To this end, we created 3 classes of genes, each designed to operate autonomously upon expression in T cells. We recently reported on the enhancing effects of constitutively active toll-like receptor 4 (caTLR4), membrane (mem) interleukin-2, memIL-12, and memIL-15, and self-oligomerizing, constitutively active CD40 (caCD40). Here, we evaluated their combined effects on peripheral blood CD8 T cells and different antimelanoma TIL cultures following mRNA electroporation. Expression in CD8 T cells induced transient production of interferon-γ and prolonged and robust upregulation of CD25, CD69, 4-1BB, and OX40. The adjuvants enhanced cytolytic activity of TILs and production of interferon-γ and TNF-α in the presence of autologous, but not mismatched, melanoma for at least 3 days after electroporation. Expression of the 3 adjuvants in young TILs from different patients markedly increased the expression of CD25, OX40, 4-1BB, CD127, and CD28 and exhibited cooperative and, at times, synergistic effects. Furthermore, predefined mixtures of mRNA encoding these adjuvants markedly enhanced the specific antitumor response of selected TILs and killing of autologous melanoma cells by young TILs. Our findings suggest that combinations of these new genetic adjuvants can substantially improve the functional properties of antitumor T cells, offering a new tool of unique versatility in adoptive cell therapy.

Potent Activation of Human T Cells by mRNA Encoding Constitutively Active CD40.

New strategies for augmenting the actual performance of therapeutic T cells in vivo are needed for improving clinical outcome of adoptive cell therapy. Cumulative findings suggest that CD40 plays an intrinsic role in T cell costimulation. Recently, we demonstrated the ability of truncated, auto-oligomerizing CD40 derivatives to induce strong activation of APCs in a ligand-independent manner. We reasoned that constitutively active CD40 (caCD40) can similarly exert enhancing effects on human antitumor T cells. To test this assumption, we transfected human T cells with in vitro-transcribed caCD40 mRNA. In polyclonal T cells, caCD40 triggered IFN-γ secretion and upregulated CD25 and 4-1BB. In antimelanoma tumor-infiltrating lymphocytes (TILs), caCD40 induced massive production of IFN-γ, exerting a pronounced synergistic effect when coexpressed with constitutively active TLR4 devoid of its extracellular ligand binding. In unselected "young" TILs, caCD40 reproducibly increased surface expression of CD25, OX40, 4-1BB, CD127, and CD28. Three days post-mRNA electroporation of CD8 TILs, caCD40 elevated IFN-γ and TNF-α production and cytolytic activity in the presence of autologous but not HLA-I-mismatched melanoma. Enhanced killing of autologous melanoma by young TILs was observed 4 d posttransfection. These findings suggest that caCD40 can function as a potent T cell adjuvant and provide essential guidelines for similar manipulation of other key members of the TNFR family.

Chronic exposure to traffic-related air pollution and cancer incidence among 10,000 patients undergoing percutaneous coronary interventions: A historical prospective study.

Background Exposure to traffic-related air pollution (TRAP) is considered to have a carcinogenic effect. The authors previously reported a nonsignificant association between TRAP and cancer risk in a relatively small cohort of myocardial infarction survivors. This study assessed whether TRAP exposure is associated with subsequent cancer in a large cohort of coronary patients. Methods & results Consecutive patients undergoing percutaneous coronary interventions in a major medical centre in central Israel from 2004 to 2014 were followed for cancer through 2015. Residential levels of nitrogen oxides (NOx) - a proxy for TRAP - were estimated based on a high-resolution national land use regression model. Cox proportional hazards models were constructed to study relationships with cancer. Among 12,784 candidate patients, 9816 had available exposure data and no history of cancer (mean age, 68 years; 77% men). During a median (25th-75th percentiles) follow-up of 7.0 (3.9-9.3) years, 773 incident cases of cancer (8%) were diagnosed. In a multivariable-adjusted model, a 10-ppb increase in mean NOx exposure was associated with hazard ratios (HRs) of 1.07 (95% confidence interval [CI] 1.00-1.15) for all-site cancer and 1.16 (95% CI 1.05-1.28) for cancers previously linked to TRAP (lung, breast, prostate, kidney and bladder). A stronger association was observed for breast cancer (HR = 1.43; 95% CI 1.12-1.83). Associations were slightly strengthened after limiting the cohort to patients with more precise exposure assessment. Conclusion Coronary patients exposed to TRAP are at increased risk of several types of cancer, particularly lung, prostate and breast. As these cancers are amenable to prevention strategies, identifying highly exposed patients may provide an opportunity to improve clinical care.