TCF1-LEF1 co-expression identifies a multipotent progenitor cell (TH2-MPP) across human allergic diseases.

Repetitive exposure to antigen in chronic infection and cancer drives T cell exhaustion, limiting adaptive immunity. In contrast, aberrant, sustained T cell responses can persist over decades in human allergic disease. To understand these divergent outcomes, we employed bioinformatic, immunophenotyping and functional approaches with human diseased tissues, identifying an abundant population of type 2 helper T (TH2) cells with co-expression of TCF7 and LEF1, and features of chronic activation. These cells, which we termed TH2-multipotent progenitors (TH2-MPP) could self-renew and differentiate into cytokine-producing effector cells, regulatory T (Treg) cells and follicular helper T (TFH) cells. Single-cell T-cell-receptor lineage tracing confirmed lineage relationships between TH2-MPP, TH2 effectors, Treg cells and TFH cells. TH2-MPP persisted despite in vivo IL-4 receptor blockade, while thymic stromal lymphopoietin (TSLP) drove selective expansion of progenitor cells and rendered them insensitive to glucocorticoid-induced apoptosis in vitro. Together, our data identify TH2-MPP as an aberrant T cell population with the potential to sustain type 2 inflammation and support the paradigm that chronic T cell responses can be coordinated over time by progenitor cells.

Digital Transfer for Hand Reconstruction in Cleft Hand and Foot Differences.

BACKGROUND: Digital transfer for hand reconstruction in children with cleft hand and foot differences present unique challenges with anomalous anatomy and rare opportunities to dramatically improve function of one- or two-digit hands. METHODS: Medical records were reviewed for patients with cleft hand and foot treated at two pediatric institutions between 1996 and 2018. Hospital records, clinical photographs, radiographs, and alginate molds were available on all patients. Patient characteristics, indications for transfer, associated syndromes, donor and recipient anatomy, and complications were examined. RESULTS: Twenty digital transfers were identified in 16 patients. The mean age at time of transfer was 6 years (range: 3-18 years). Associated syndromes in this study included ectrodactyly ectodermal dysplasia clefting (EEC) syndrome and Goltz's syndrome. Recipient sites included the thumb (n = 17) and index ray (n = 3) in 10 hands with monodactyly, 6 hands with a two-digit ulnar syndactyly, and 3 hands with central deficiency and associated polydactyly or other anomalies. Donor sites included the great toe (n = 7), fifth toe (n = 9), great toe polydactyly (n = 2), thumb polydactyly (n = 1), and second toe (n = 1). All transfers survived. Revisions included tenolysis (n = 2), repeat fixation for nonunion or malunion (n = 2), and fusion for instability (n = 3). CONCLUSION: Digital transfer in cleft hand and foot patients is a functional endeavor. The transferred digits provide sensation, mobility, and stability for opposition. Technically challenging due to small structures and atypical anatomy, these rare cases represent unique opportunities to improve function and appearance in the pediatric hand. This is a therapeutic study and reflects level of evidence IV.

Quantitative microinjection using fluorescence calibration of streaming microdroplets on a superhydrophobic surface.

A simple and reproducible procedure was developed to measure the volume of liquid microinjected into cells. A calibration curve of droplet fluorescence intensity versus volume was constructed by injecting a fluorescent dextran solution through a 125-150 µm diameter micropipette into an oil-filled culture dish to create a spray of varied-sized droplets. The droplets retained a spherical shape because they were in an oil medium and they settled onto a glass surface coated with a superhydrophobic surface. Fluorescent micrographs of the droplets were obtained and analyzed with Image-J software to quantify the fluorescence intensity and radius of each spherical droplet to produce the calibration curve. Subsequently, Dut-145 human prostate carcinoma cells were microinjected with the same fluorescent dextran solution and fluorescent micrographs of the cells were obtained using the identical exposure conditions used to photograph the droplets. The measured fluorescence intensity of the microinjected cells was entered into the formula for the regression line that was fit to the calibration curve allowing determination of the volume of solution injected into each cell. Thus, a mixture consisting of known concentrations of a test material of test material (macromolecules, drugs, etc.) and a fluorescent dextran, volumetric, tracer can be used to quantify the relationship between the amount of a microinjected material and subsequent effects on cells.

Coronary Artery Disease Association With Arterial Calcifications on Routine Hand Radiographs.

PURPOSE: Arterial calcifications in the lower extremity, chest, and cardiac vessels have been linked to coronary artery disease (CAD). However, the relation between arterial calcifications observed on routine hand and upper-extremity radiographs and atherosclerosis has not been determined. This study examined whether arterial calcifications found on hand radiographs are associated with CAD. METHODS: A record review from a single institution identified 345 patients with both hand radiographs and CAD screening with cardiac stress testing or coronary angiography. Patients with chronic kidney disease, end-stage renal disease, or incomplete hand films were excluded. We reviewed x-rays for findings of arterial calcifications. Cardiac testing results were used to establish a baseline diagnosis of CAD. We made group comparisons and employed multivariable logistic regression to evaluate the association between upper-extremity calcification and CAD. RESULTS: A total of 210 patients met inclusion criteria: 155 with CAD and 55 without it. Mean age was 72 years, body mass index was 28.8, and 54% were male. Patients had comorbidities of hypertension (91%), hyperlipidemia (87%), diabetes (39%), cerebrovascular accident (9%), and a history of tobacco use (53%). Of 155 CAD patients, 67 had arterial calcifications on hand radiographs (43%), compared with 6 of 55 without it (11%). In a multivariable model controlling for sex, hyperlipidemia, and diabetes, the presence of arterial calcifications on hand plain films indicated a 6.2-fold increased odds of CAD. CONCLUSIONS: The current data demonstrate that arterial calcifications on hand radiographs are independently associated with CAD. This may represent an opportunity to the treating physician as a point of referral or investigation for underlying or occult CAD. TYPE OF STUDY/LEVEL OF EVIDENCE: Prevalence III.

Reconstruction of quadriceps function with composite free tissue transfers following sarcoma resection.

BACKGROUND AND OBJECTIVES Wide margin resection of a soft tissue sarcoma (STS) may require extensive removal of quadriceps muscle with or without the knee extensor mechanism. The objective of this study is to present present the use of a combined functional muscle transfer and soft tissue coverage through the use of chimeric anterolateral thigh flaps. METHODS: Patients were retrospectively reviewed who underwent deep STS resection of the anterior compartment of the thigh with functional reconstruction of knee extension using a contralateral free anterolateral thigh (ALT) flap. RESULTS: Three patients with an average age 53.6 years (range: 33-66) were included. Average follow-up was 82 weeks (76-92 months). Full active extension was regained in 66% of patients with all patients regaining active extensor capabilities beyond 100°. The mean Knee Society Score was 83.3 (range; 76-92) and Musculoskeletal Tumor Society Score 21.6 (range; 19-21). Isometric knee extensor strength exceeded 4+/5 in all patients. CONCLUSION: Following soft tissue sarcoma resections of the lower extremity, chimeric anterolateral thigh flaps for restoration of knee extension can provide significant improvements in the potential for ambulation and regaining quadriceps function.

Surgeon-Based 3D Printing for Microvascular Bone Flaps.

Background Three-dimensional (3D) printing has developed as a revolutionary technology with the capacity to design accurate physical models in preoperative planning. We present our experience in surgeon-based design of 3D models, using home 3D software and printing technology for use as an adjunct in vascularized bone transfer. Methods Home 3D printing techniques were used in the design and execution of vascularized bone flap transfers to the upper extremity. Open source imaging software was used to convert preoperative computed tomography scans and create 3D models. These were printed in the surgeon's office as 3D models for the planned reconstruction. Vascularized bone flaps were designed intraoperatively based on the 3D printed models. Results Three-dimensional models were created for intraoperative use in vascularized bone flaps, including (1) medial femoral trochlea (MFT) flap for scaphoid avascular necrosis and nonunion, (2) MFT flap for lunate avascular necrosis and nonunion, (3) medial femoral condyle (MFC) flap for wrist arthrodesis, and (4) free fibula osteocutaneous flap for distal radius septic nonunion. Templates based on the 3D models allowed for the precise and rapid contouring of well-vascularized bone flaps in situ, prior to ligating the donor pedicle. Conclusions Surgeon-based 3D printing is a feasible, innovative technology that allows for the precise and rapid contouring of models that can be created in various configurations for pre- and intraoperative planning. The technology is easy to use, convenient, and highly economical as compared with traditional send-out manufacturing. Surgeon-based 3D printing is a useful adjunct in vascularized bone transfer. Level of Evidence Level IV.

The "Superior Ledge": a Modification of the Standard Superomedial Pedicle Reduction Mammoplasty to Accentuate Nipple-Areola Complex Projection.

BACKGROUND: The superomedial pedicle parenchymal excision pattern for reduction mammaplasty has the benefits of a reproducible breast shape and improved superomedial fullness, but is limited by a susceptibility to nipple retraction. The senior author of this paper has formalized the "superior ledge" modification of the superomedial pedicle technique (SL-SMP) to address these limitations. OBJECTIVE: To describe the technical details of the SL-SMP breast reduction technique and to analyze patient outcomes. METHODS: The technique involves only partial-thickness parenchymal excision superolateral to the pedicle, thereby leaving a "superior ledge" of parenchyma on top of which the nipple-areola complex (NAC) rests in a tension-free manner. Postoperative photographs were recorded; and patient demographics, intraoperative details, complications, and outcomes were recorded and analyzed. RESULTS: One hundred seven patients underwent SL-SMP reduction mammaplasty between 2007 and 2013. Complications included wound-healing complications (9.3 %), infection (2.8 %), seroma (1.9 %), and hematoma (1.9 %). Mean follow-up was 44.6 months (Range: 17-72), and during that period no incidence of clinically relevant NAC retraction was noted by either the patient or surgical team. CONCLUSIONS: Maintenance of a distinct superior ledge underlying the final position of the NAC is an important modification to stress, to prevent nipple retraction. Importantly, the height of the ledge can be personalized for each patient. We feel it is a valuable addition to the plastic surgeon's armamentarium to optimize outcomes for patients seeking relief from excessive breast tissue. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Pulsed electromagnetic fields dosing impacts postoperative pain in breast reduction patients.

BACKGROUND: Pulsed electromagnetic fields (PEMF) reduce postoperative pain and narcotic requirements in breast augmentation, reduction, and reconstruction patients. PEMF enhances both calmodulin-dependent nitric oxide and/or cyclic guanosine monophosphate signaling and phosphodiesterase activity, which blocks cyclic guanosine monophosphate. The clinical effect of these competing responses on PEMF dosing is not known. METHODS: Two prospective, nonrandomized, active cohorts of breast reduction patients, with 15 min PEMF per 2 h; "Q2 (active)", and 5 min PEMF per 20 min; "5/20 (active)", dosing regimens were added to a previously reported double-blind clinical study wherein 20 min PEMF per 4 h, "Q4 (active)", dosing significantly accelerated postoperative pain reduction compared with Q4 shams. Postoperative visual analog scale pain scores and narcotic use were compared with results from the previous study. RESULTS: Visual analog scale scores at 24 h were 43% and 35% of pain at 1 h in the Q4 (active) and Q2 (active) cohorts, respectively (P < 0.01). Pain at 24 h in the 5/20 (active) cohort was 87% of pain at 1 h, compared with 74% in the Q4 (sham) cohort (P = 0.451). Concomitantly, narcotic usage in the 5/20 (active) and Q4 (sham) cohorts was not different (P = 0.478), and 2-fold higher than the Q4 (active) and Q2 (active) cohorts (P < 0.02). CONCLUSIONS: This prospective study shows Q4/Q2, but not 5/20 PEMF dosing, accelerated postoperative pain reduction compared with historical shams. The 5/20 (active) regimen increases NO 4-fold faster than the Q4 (active) regimen, possibly accelerating phosphodiesterase inhibition of cyclic guanosine monophosphate sufficiently to block the PEMF effect. This study helps define the dosing limits of clinically useful PEMF signals.

Pectoralis major myocutaneous flap versus free fasciocutaneous flap for reconstruction of partial hypopharyngeal defects: what should we be doing?

BACKGROUND: Partial hypopharyngeal defects are most commonly reconstructed with the pectoralis major myocutaneous flap (PMMF) or free fasciocutaneous (FFC) flap. The purpose of this study is to determine the ideal method for reconstruction of partial hypopharyngeal defects by reviewing our institutional experience and the literature. METHODS: A retrospective review of partial hypopharyngeal reconstructions since 2009 was performed. A National Library of Medicine search of studies on partial hypopharyngeal reconstruction since 1988 was performed. Data on complications, diet, and speech were extracted and pooled. RESULTS: A total of 18 patients were studied-9 had PMMF reconstruction and 9 had FFC reconstruction. Operative time (8.75 vs. 13.0 hours, p = 0.0003) was shorter in the PMMF group. Pharyngocutaneous fistula developed in one PMMF patient (11.1%) and two FFC patients (22.2%). Late strictures occurred in three PMMF patients. Six patients in each group (66.7%) progressed to a regular diet. Three patients in each group produced tracheoesophageal speech after TEP. Literature review identified 36 relevant studies, with 301 patients reconstructed with PMMF and 605 patients with FFC. Pooled-data analysis revealed that PMMF had higher reported rates of fistula (24.7 vs. 8.9%, p < 0.0001) and requirement for second surgery (11.3 vs. 5.5%, p = 0.04). There was no difference in stricture rates or progression to regular diet. Fewer PMMF patients produced tracheoesophageal speech (17.5 vs. 52.1%, p < 0.0001). CONCLUSIONS: PMMF and FFC flaps are valid approaches to reconstructing partial hypopharyngeal defects, though rates in the literature of fistula, need for revisional surgery, and tracheoesophageal speech after laryngectomy are more favorable after free flap reconstruction.

Bilateral Implant-based Breast Reconstruction with Unilateral Radiotherapy: A Matched Cohort Study Comparing Nipple-sparing Mastectomy and Skin-sparing Mastectomy.

Background: Nipple-sparing mastectomy (NSM) preserves the natural nipple-areola complex and entire native breast skin, with the goal of better cosmetic outcomes in breast reconstruction. In bilateral TE/implant-based reconstruction requiring unilateral postmastectomy radiotherapy (PMRT), progressive radiation-induced fibrosis can lead to increasing nipple asymmetry with cosmetic dissatisfaction. Thus, PMRT may ultimately negate the intended positive cosmetic value of NSM compared with skin-sparing mastectomy (SSM). This study compares (1) surgical complications, (2) patient satisfaction, and (3) aesthetic outcomes between NSM versus SSM in bilateral implant-based reconstruction with unilateral PMRT. Methods: This retrospective matched cohort study included consecutive NSM patients with bilateral TE/implant breast reconstruction + unilateral PMRT matched 1:2 to SSM group. Patients completed PMRT and TE exchange to implants. Demographics, oncologic stage, comorbidities, and complications were collected. Patient satisfaction was evaluated by BREAST-Q. Aesthetic outcomes were assessed by blinded reviewers with a five-point Likert scale. Results: Among 58 patients who underwent bilateral TE/implant reconstruction with unilateral PMRT, 17 NSM patients were matched to 41 SSM patients by age, body mass index, and comorbidities. No significant differences existed in overall surgical complications and individual BREAST-Q questionnaire scores between cohorts. However, aesthetic outcomes scores were higher in SSM compared with NSM. Conclusions: Although NSM is generally associated with superior cosmetic outcomes compared with SSM, it has far less impact in bilateral implant-based breast reconstruction with unilateral PMRT due to the negative postradiotherapy effect on nipple symmetry.

The 3-4 loop of an archaeal glutamate transporter homolog experiences ligand-induced structural changes and is essential for transport.

Glutamatergic synaptic transmission is terminated by members of the excitatory amino acid transporter (EAAT) family of proteins that remove glutamate from the synaptic cleft by transporting it into surrounding glial cells. Recent structures of a bacterial homolog suggest that major motions within the transmembrane domain translocate the substrate across the membrane. However, the events leading to this large structural rearrangement are much less clear. Two reentrant loops have been proposed to act as extracellular and intracellular gates, but whether other regions of these proteins play a role in the transport process is unknown. We hypothesized that transport-related conformational changes could change the solvent accessibilities of affected residues, as reflected in protease sensitivity or small-molecule reactivity. In the model system Glt(Ph), an archaeal EAAT homologue from Pyrococcus horikoshii, limited trypsin proteolysis experiments initially identified a site in the long extracellular loop that stretches between helices 3 and 4 that becomes protected from proteolysis in the presence of a substrate, L-aspartate, or an inhibitor, DL-TBOA in the presence of Na(+), the cotransported ion. Using a combination of site-directed cysteine-scanning mutagenesis and fluorescein-5-maleimide labeling we found that positions throughout the loop experience these ligand-induced conformational changes. By selectively cleaving the 3-4 loop (via introduced Factor Xa sites) we demonstrate that it plays a vital role in the transport process; though structurally intact, the cleaved proteins are unable to transport aspartate. These results inculcate the 3-4 loop as an important player in the transport process, a finding not predicted by any of the available crystal structures of Glt(Ph).

Making the Case for Virtual Surgical Planning: Bilateral Sequential Fibula Flaps with Immediate Dental Implants for Maxillectomy.

SUMMARY: Oncologic maxillectomy defects requiring bony reconstruction are among the most challenging head and neck cases because of the complex three-dimensional geometry of the midface. Virtual surgical planning technology is advantageous in these cases because it provides superior positional precision and accuracy compared with traditional techniques and facilitates prosthodontic rehabilitation. Maxillary cancer recurrence after an initial fibula flap reconstruction presents a unique challenge. The authors report the first two cases of sequential fibula flaps after second or recurrent cancer of the maxilla. Virtual surgical planning facilitated resection with adequate tumor margins, optimized anatomic positioning of the fibula construct with three-dimensional printed plates, and enabled immediate functional dental implant placement.

The effects of human following behaviours on decision making during aperture crossing scenarios.

BACKGROUND: Everyday locomotion often requires that we navigate crowded and cluttered environments. Individuals navigating through nonconfined space will require a deviation from the straight path in order to avoid apertures smaller than 1.4 times their shoulder width. When in a crowd, humans will follow the behaviours of those directly in front of them, making changes to their walking speed and direction heading based on the changes made by the people they are following. RESEARCH QUESTION: The current study aimed to discover whether the decisions made by young adults regarding the passability of an aperture would be influenced by the presence of a leader completing the same nonconfined aperture crossing task. METHODS: Participants (N = 24) walked in a virtual reality environment along a 6.5 m pathway towards a goal while avoiding two virtual poles which created an aperture (0.8-1.8 times the participants' shoulder widths). For some trials, a sex-matched avatar (shoulder width of 0.8, 1.0, or 1.2 times the participants' shoulder widths) completed the aperture crossing task, using its own body-scaled information, ahead of the participant. RESULTS: Participants walked through apertures smaller than 1.4 times their shoulder width (i.e. critical point) regardless of avatars' independent behaviours. Participants began to deviate 3.69 m from the aperture on all trials that required a deviation and approached their goal at a slower speed when the avatar was present. SIGNIFICANCE: This study demonstrates that during a nonconfined aperture crossing task, individuals are not influenced by human following behaviours and will continue to make decisions based on their own body-scaled information.

Plastic Surgical Management of Hidradenitis Suppurativa.

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Describe the pathogenesis of hidradenitis suppurativa. 2. Discuss perioperative multimodal therapy of hidradenitis suppurativa, including medical optimization. 3. Determine an appropriate surgical plan with excision and reconstruction based on hidradenitis suppurativa severity, size, and anatomical location. SUMMARY: Successful treatment of hidradenitis suppurativa requires a multidisciplinary team approach and multimodal therapy.

Recent Advances in Implant-Based Breast Reconstruction.

LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Understand the indications for implant-based breast reconstruction and the indications for nipple preservation compared to skin-sparing or skin-reducing patterns. 2. Understand the indications for direct-to-implant breast reconstruction versus tissue expander/implant breast reconstruction and the advantages and disadvantages of total, partial, or no muscle coverage. 3. Understand the role of acellular dermal matrix or mesh in reconstruction. 4. Learn the advantages and disadvantages of different types and styles of implants and develop a postoperative plan for care and pain management. SUMMARY: Breast reconstruction with implants has seen a decade of advances leading to more natural breast reconstructions and lower rates of complications.

Histone Modifications as Biomarkers for Immunotherapy.

Recent advances in immunotherapy have revolutionized the treatment of certain cancers. Some patients show a durable response to these immunotherapies, while others show little benefit or develop resistance. Identification of biomarkers to predict responsiveness will be helpful for informing treatment strategies; and would furthermore lead to the identification of molecular pathways dysregulated in nonresponding patients that could be targeted for therapeutic development. Pathways of epigenetic modification, such as histone posttranslational modifications (PTMs), have been shown to be dysregulated in certain cancer and immune cells. Histones are abundant cellular proteins readily assayed with high-throughput technologies, making them attractive targets as biomarkers. We explore promising advancements for using histone PTMs as immunotherapy responsiveness biomarkers in both cancer and immune cells, and provide a methodological workflow for assaying histone PTMs in relevant samples.

Proteogenomic analysis of melanoma brain metastases from distinct anatomical sites identifies pathways of metastatic progression.

Melanoma brain metastases (MBM) portend a grim prognosis and can occur in up to 40% of melanoma patients. Genomic characterization of brain metastases has been previously carried out to identify potential mutational drivers. However, to date a comprehensive multi-omics approach has yet to be used to analyze brain metastases. In this case report, we present an unbiased proteogenomics analyses of a patient's primary skin cancer and three brain metastases from distinct anatomic locations. We performed molecular profiling comprised of a targeted DNA panel and full transcriptome as well as proteomics using mass spectrometry. Phylogeny demonstrated that all MBMs shared a SMARCA4 mutation and deletion of 12q. Proteogenomics identified multiple pathways upregulated in the MBMs compared to the primary tumor. The protein, PIK3CG, was present in many of these pathways and had increased gene expression in metastatic melanoma tissue from the cancer genome atlas data. Proteomics demonstrated PIK3CG levels were significantly increased in all 3 MBMs and this finding was further validated by immunohistochemistry. In summary, this case report highlights the potential role of proteogenomics in identifying pathways involved in metastatic tumor progression. Furthermore, our multi-omics approach can be considered to aid in precision oncology efforts and provide avenues for therapeutic innovation.

Epigenetic Control of Cdkn2a.Arf Protects Tumor-Infiltrating Lymphocytes from Metabolic Exhaustion.

T-cell exhaustion in cancer is linked to poor clinical outcomes, where evidence suggests T-cell metabolic changes precede functional exhaustion. Direct competition between tumor-infiltrating lymphocytes (TIL) and cancer cells for metabolic resources often renders T cells dysfunctional. Environmental stress produces epigenome remodeling events within TIL resulting from loss of the histone methyltransferase EZH2. Here, we report an epigenetic mechanism contributing to the development of metabolic exhaustion in TIL. A multiomics approach revealed a Cdkn2a.Arf-mediated, p53-independent mechanism by which EZH2 inhibition leads to mitochondrial dysfunction and the resultant exhaustion. Reprogramming T cells to express a gain-of-function EZH2 mutant resulted in an enhanced ability of T cells to inhibit tumor growth in vitro and in vivo. Our data suggest that manipulation of T-cell EZH2 within the context of cellular therapies may yield lymphocytes that are able to withstand harsh tumor metabolic environments and collateral pharmacologic insults. SIGNIFICANCE: These findings demonstrate that manipulation of T-cell EZH2 in cellular therapies may yield cellular products able to withstand solid tumor metabolic-deficient environments. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/21/4707/F1.large.jpg.

Loss of E-Cadherin Inhibits CD103 Antitumor Activity and Reduces Checkpoint Blockade Responsiveness in Melanoma.

Identifying controlling features of responsiveness to checkpoint blockade therapies is an urgent goal in oncology research. Our group and others have previously shown melanoma tumors resistant to checkpoint blockade display features of mesenchymal transition, including E-cadherin loss. Here, we present the first in vivo evidence that E-cadherin from tumor cells facilitate immune attack, using a B16F10 melanoma mouse model in which E-cadherin is exogenously expressed (B16.Ecad). We find, compared with vector control, B16.Ecad exhibits delayed tumor growth, reduced metastatic potential, and increased overall survival in vivo. Transplantation of B16.Ecad into Rag1-/- and CD103-/- mice abrogated the tumor growth delay. This indicates the anti-melanoma response against B16.Ecad is both immune and CD103+ mediated. Moreover, B16.Ecad showed increased responsiveness to combination immune checkpoint blockade (ICB) compared with vector control. This work establishes a rationale for ICB responses observed in high E-cadherin-expressing tumors and suggests therapeutic advancement through amplifying CD103+ immune cell subsets.Significance: These findings identify the mechanism behind checkpoint blockade resistance observed in melanoma that has undergone mesenchymal transition and suggest activation of CD103+ immune cells as a therapeutic strategy against other E-cadherin-expressing malignancies.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/6/1113/F1.large.jpg.