Cancer Immunosurveillance by Tissue-Resident Innate Lymphoid Cells and Innate-like T Cells.

Malignancy can be suppressed by the immune system in a process termed immunosurveillance. However, to what extent immunosurveillance occurs in spontaneous cancers and the composition of participating cell types remains obscure. Here, we show that cell transformation triggers a tissue-resident lymphocyte response in oncogene-induced murine cancer models. Non-circulating cytotoxic lymphocytes, derived from innate, T cell receptor (TCR)αß, and TCRγδ lineages, expand in early tumors. Characterized by high expression of NK1.1, CD49a, and CD103, these cells share a gene-expression signature distinct from those of conventional NK cells, T cells, and invariant NKT cells. Generation of these lymphocytes is dependent on the cytokine IL-15, but not the transcription factor Nfil3 that is required for the differentiation of tumor-infiltrating NK cells, and IL-15 deficiency, but not Nfil3 deficiency, results in accelerated tumor growth. These findings reveal a tumor-elicited immunosurveillance mechanism that engages unconventional type-1-like innate lymphoid cells and type 1 innate-like T cells.

Graded Foxo1 activity in Treg cells differentiates tumour immunity from spontaneous autoimmunity.

Regulatory T (Treg) cells expressing the transcription factor Foxp3 have a pivotal role in maintaining immunological self-tolerance; yet, excessive Treg cell activities suppress anti-tumour immune responses. Compared to the resting Treg (rTreg) cell phenotype in secondary lymphoid organs, Treg cells in non-lymphoid tissues exhibit an activated Treg (aTreg) cell phenotype. However, the function of aTreg cells and whether their generation can be manipulated are largely unexplored. Here we show that the transcription factor Foxo1, previously demonstrated to promote Treg cell suppression of lymphoproliferative diseases, has an unexpected function in inhibiting aTreg-cell-mediated immune tolerance in mice. We find that aTreg cells turned over at a slower rate than rTreg cells, but were not locally maintained in tissues. aTreg cell differentiation was associated with repression of Foxo1-dependent gene transcription, concomitant with reduced Foxo1 expression, cytoplasmic localization and enhanced phosphorylation at the Akt sites. Treg-cell-specific expression of an Akt-insensitive Foxo1 mutant prevented downregulation of lymphoid organ homing molecules, and impeded Treg cell homing to non-lymphoid organs, causing CD8(+) T-cell-mediated autoimmune diseases. Compared to Treg cells from healthy tissues, tumour-infiltrating Treg cells downregulated Foxo1 target genes more substantially. Expression of the Foxo1 mutant at a lower dose was sufficient to deplete tumour-associated Treg cells, activate effector CD8(+) T cells, and inhibit tumour growth without inflicting autoimmunity. Thus, Foxo1 inactivation is essential for the migration of aTreg cells that have a crucial function in suppressing CD8(+) T-cell responses; and the Foxo signalling pathway in Treg cells can be titrated to break tumour immune tolerance preferentially.

Foxp3-independent mechanism by which TGF-ß controls peripheral T cell tolerance.

Peripheral T cell tolerance is promoted by the regulatory cytokine TGF-ß and Foxp3-expressing Treg cells. However, whether TGF-ß and Treg cells are part of the same regulatory module, or exist largely as distinct pathways to repress self-reactive T cells remains incompletely understood. Using a transgenic model of autoimmune diabetes, here we show that ablation of TGF-ß receptor II (TßRII) in T cells, but not Foxp3 deficiency, resulted in early-onset diabetes with complete penetrance. The rampant autoimmune disease was associated with enhanced T cell priming and elevated T cell expression of the inflammatory cytokine GM-CSF, concomitant with pancreatic infiltration of inflammatory monocytes that triggered immunopathology. Ablation of the GM-CSF receptor alleviated the monocyte response and inhibited disease development. These findings reveal that TGF-ß promotes T cell tolerance primarily via Foxp3-independent mechanisms and prevents autoimmunity in this model by repressing the cross talk between adaptive and innate immune systems.

Characterizing Long-Term Swallowing and Voice Outcomes Following Anterior Transcervical Approach.

OBJECTIVES: (1) Assess the frequency and severity of long-term swallowing and voice complaints, follow-up care, risk factors for the development of long-term swallowing and voice complications in patients who underwent anterior transcervical approach (ACA). (2) Determine incidence of long-term swallowing and voice complications requiring follow-up otolaryngologic care and assess the frequency of otolaryngologic follow-up for postoperative swallowing and voice complaints. METHODS: Retrospective cohort study of patients between January 2017 and March 2020 who underwent ACA. Demographic information, data from preoperative evaluation, operative records, and data from postoperative visits were collected. Patients were contacted to complete the Eating Assessment Tool and the "Impairment" subset of the Voice Symptoms Scale. RESULTS: A total of 48 patients (10.6%) followed up with a head and neck surgeon for swallowing complaints and 31 patients (6.8%) for voice complaints. Otolaryngology follow-up for swallowing complaints among patients with at least 3 and 12 months of follow-up was 16.4% and 17.8%, respectively. Otolaryngology follow-up for voice complaints among patients with at least 3 and 12 months of follow-up was 11.7% and 11.9%, respectively. Swallowing function was abnormal in 40.7% at least 3 months after surgery and in 41.8% 12 months after. Voice function was abnormal in 55.7% of respondents at least 3 months after surgery and in 54.5% of respondents 12 months after. CONCLUSIONS: ACA is associated with otolaryngologic complications that include dysphagia and dysphonia. This study demonstrates that long-term swallowing and voice dysfunction appear to persist longer than what is noted by patient utilization of follow-up otolaryngologic care. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:3201-3205, 2024.

An Assessment of Race as a Risk Factor for Doxorubicin-Related Cardiotoxicity in Diffuse Large B-Cell Lymphoma.

BACKGROUND: Doxorubicin carries a risk of congestive heart failure (CHF). Black race has been suggested as a risk factor for doxorubicin-related cardiotoxicity, but data are limited. We assessed whether HF occurs at higher rates in Black patients compared to White patients who receive doxorubicin for DLBCL, and evaluated race as an independent risk factor for the development of HF after adjusting for known risk factors. PATIENTS AND METHODS: We used SEER-Medicare to identify patients 66 years and older with DLBCL. We excluded patients with CHF documented prior to diagnosis with DLBCL. We assessed for hypertension, type 2 diabetes, coronary artery disease, and arrhythmias prior to diagnosis with DLBCL. The primary outcome was documented CHF at any point following DLBCL diagnosis. Secondary outcomes included CHF in the first year following diagnosis and death. We performed analyses additionally stratified by cumulative dose of doxorubicin. RESULTS: Our study population consisted of 8,604 patients (White 96.8%, Black 3.2%). In both Kaplan-Meier and competing risk analyses, we observed no significant difference in the incidence of CHF between Black and White patients, both before and after adjusting for covariates. Finally, we observed no significant differences in the incidence of CHF by race after stratification by cumulative doxorubicin dose. CONCLUSIONS: CHF is common following doxorubicin chemotherapy for DLBCL in older patients. No association was observed between Black race and the onset of heart failure in this setting. Rigorous screening for known clinical risk factors is likely more relevant than race in treatment selection and optimization.

Evaluating the impact of eligibility criteria in first-line clinical trials for follicular lymphoma: a MER/LEO cohort analysis.

Cancer clinical trial eligibility criteria may create patient populations studied in trials that do not reflect the patient populations treated in the real-world setting. Follicular lymphoma (FL) is an indolent lymphoma with heterogeneous presentations across a broad range of individuals, resulting in many acceptable management strategies. We evaluated how first-line clinical trial eligibility criteria impacted the demographic makeup and outcomes of patients with FL for whom systemic therapy might be considered. We compared the characteristics of 196 patients with FL from a single institution to eligibility criteria from 10 first-line FL trials on clinicaltrials.gov. Next, we tabulated eligibility criteria from 24 first-line FL protocols and evaluated their impact on 1198 patients with FL with stages II to IV disease from the prospective Molecular Epidemiology Resource (MER) and Lymphoma Epidemiology of Outcomes (LEO) cohort studies. We found that 39.8% and 52.7% of patients with FL might be excluded from clinical trials based on eligibility criteria derived from clinicaltrials.gov and protocol documents, respectively. Patients excluded because of renal function, prior malignancy, and self-reported serious health conditions tended to be older. Expanding stage requirement from III-IV to II-IV, and platelet requirement from ≥150 000 to ≥75 000 increased population size by 21% and 8%, respectively, in MER and by 16% and 13%, respectively, in LEO, without impacting patient demographics or outcomes. These data suggest that management of older individuals with FL may not be fully informed by recent clinical trials. Moreover, liberalizing stage and platelet criteria might expand the eligible population and allow for quicker trial accrual without impacting outcomes.

Measurement of hindered diffusion in complex geometries for high-speed studies of single-molecule forces.

In a high-speed single-molecule experiment with a force probe, a protein is tethered between two substrates that are manipulated to exert force on the system. To avoid nonspecific interactions between the protein and nearby substrates, the protein is usually attached to the substrates through long, flexible linkers. This approach precludes measurements of mechanical properties with high spatial and temporal resolution, for rapidly exerted forces are dissipated into the linkers. Because mammalian hearing operates at frequencies reaching tens to hundreds of kilohertz, the mechanical processes that occur during transduction are of very short duration. Single-molecule experiments on the relevant proteins therefore cannot involve long tethers. We previously characterized the mechanical properties of protocadherin 15 (PCDH15), a protein essential for human hearing, by tethering an individual monomer through very short linkers between a probe bead held in an optical trap and a pedestal bead immobilized on a glass coverslip. Because the two confining surfaces were separated by only the length of the tethered protein, hydrodynamic coupling between those surfaces complicated the interpretation of the data. To facilitate our experiments, we characterize here the anisotropic and position-dependent diffusion coefficient of a probe in the presence of an effectively infinite wall, the coverslip, and of the immobile pedestal.

Lymphoma Study Titles on ClinicalTrials.gov Lack Details Necessary for Study Identification.

BACKGROUND: ClinicalTrials.gov is used by clinicians and patients to identify clinical trials. We assessed the ease with which users could identify relevant trials related to lymphoma using the short and official titles. We hypothesized that lymphoma titles frequently lack important information. MATERIALS AND METHODS: We performed 2 searches on ClinicalTrials.gov. The first search was performed before June 2017, when ClinicalTrials.gov underwent updates to improve usability. The second was performed after 2017. We assessed whether the short and official titles of each trial provided information on the study phase, eligible disease status, lymphoma histologic subtype, study intervention, primary objective, and the presence of randomization and placebo control. RESULTS: Of the pre-overhaul lymphoma trials, the official versus short titles included information regarding study intervention (99% vs. 96%), study phase (82% vs. 14%), lymphoma histologic subtype (78% vs. 72%), disease status (46% vs. 35%), randomization (13% vs. 2%), presence of placebo (6% vs. 2%), and primary objective (38% vs. 26%). Of the post-overhaul trials, the official versus short titles included information regarding study intervention (97% vs. 96%), lymphoma histologic subtype (83% vs. 78%), study phase (78% vs. 8%), disease status (64% vs. 50%), primary objective (38% vs. 23%), presence of placebo (11% vs. 0%), and randomization (18% vs. 0%). CONCLUSION: The official titles were more informative than were the short titles on ClinicalTrials.gov. However, the short and official titles both often lacked the basic information needed to understand a clinical trial. This has persisted despite updates to the platform. These results highlight the need for standardization of the format and content included in study titles.

Patterns of survival in patients with recurrent mantle cell lymphoma in the modern era: progressive shortening in response duration and survival after each relapse.

As the survival of patients with mantle cell lymphoma (MCL) continues to improve, patients are increasingly being treated with multiple regimens. However, outcome after each line remains poorly characterized in the modern era. To address this knowledge gap, we retrospectively studied 404 consecutive MCL patients who were managed between 2000 and 2014 at Memorial Sloan Kettering Cancer Center. Histologic diagnosis was centrally confirmed, and patients were followed longitudinally from diagnosis throughout their disease course. Progression-free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier method. The median OS and PFS after first-line treatment were 9.7 and 4.0 years, respectively. After second-line therapy, the median OS and PFS were 41.1 and 14.0 months, third line were 25.2 and 6.5 months, and fourth line were 14.4 and 5.0 months. In patients less than 65 years, stem cell transplant (SCT)-based frontline regimens were associated with improved PFS compared with non-SCT regimens (median PFS: 86.2 versus 40.0 months; P < 0.01), with a trend toward longer OS (median OS: 165.0 versus 120.0 months; P = 0.06). Early treatment failure after first-line regimens was associated with worse OS (5.9 versus 2.5 years; P < 0.01). Our study should facilitate establishing proper endpoints for future clinical trials using novel treatment approaches.

Ets transcription factor GABP controls T cell homeostasis and immunity.

Peripheral T cells are maintained in the absence of vigorous stimuli, and respond to antigenic stimulation by initiating cell cycle progression and functional differentiation. Here we show that depletion of the Ets family transcription factor GA-binding protein (GABP) in T cells impairs T-cell homeostasis. In addition, GABP is critically required for antigen-stimulated T-cell responses in vitro and in vivo. Transcriptome and genome-wide GABP-binding site analyses identify GABP direct targets encoding proteins involved in cellular redox balance and DNA replication, including the Mcm replicative helicases. These findings show that GABP has a nonredundant role in the control of T-cell homeostasis and immunity.