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Fig. S1. Establishment of SB-3123 murine melanoma model. Fig. S2. Schematic of primer design for BRAF c.1799T > A (V600E) mutation analysis in SB-3123p murine melanoma cells. Fig. S3. SB-3123p melanoma is highly sensitive to vemurafenib. Fig. S4. BRAFV600E specific effect of vemurafenib upon SB-3123p established melanomas. Fig. S5. Establishment of SB-3123 murine melanoma cells expressing mouse gp100. Fig. S6. Concurrent vemurafenib therapy is required for sustained tumor growth control. Fig. S7. SB-3123 proliferative capacity is reduced when cultured under combinatorial conditions of vemurafenib and IFN-γ/TNF-α cytokines. Fig. S8. Isobologram analysis from our 8x8 screen for the synergistic (black circle) drug combination of vemurafenib + IFN-γ/TNF-α. Fig. S9. IFN-γ and TNF-α combined with vemurafenib induce growth arrest of SB-3123 melanoma cells. Fig. S10. Melanoma proliferative capacity is reduced when cultured under combinatorial conditions of vemurafenib and IFN-γ/TNF-α cytokines in a BRAFV600E dependent manner. Fig. S11. Human melanoma proliferative capacity is reduced when cultured under combinatorial conditions of vemurafenib and IFN-γ/TNF-α cytokines in a BRAFV600E dependent manner. Fig. S12. Gene set enrichment analysis of vemurafenib + IFN-γ/TNF-α dependent gene expression signature enriched in genes induced by IFN-γ/TNF-α treatment of SB3123. Supplementary Table 1 - All Genes, One Way Anova p FDR < 0.05 - Gene Cluster 1. Supplementary Table 2 - All Genes, One Way Anova p FDR < 0.05 - Gene Cluster 2. Supplementary Table 3 - All Genes, One Way Anova p FDR < 0.05 - Gene Cluster 3. Supplementary Table 4 - All Genes, One Way Anova p FDR < 0.05 - Gene Cluster 4. Supplementary Table 5 - All Genes, One Way Anova p FDR < 0.05 - Gene Cluster 5. Table S6. Gene set enrichment analysis of vemurafenib + IFN-γ/TNF-α dependent gene expression signature normalized to the vemurafenib only dependent gene expression signature in SB3123. Table S7. Gene set enrichment analysis of vemurafenib + IFN-γ/TNF-α dependent gene expression signature normalized to the IFN- γ/TNF-α only dependent gene expression signature in SB3123. Table S8. Gene set enrichment analysis of vemurafenib dependent gene expression signature normalized to control treated SB3123. Supplementary Table 9 - IFNy/TNFB induced genes vs Control Treatment, fold change > 2.0, p-value < 0.01. Supplementary Table 10 - Vemurafenib induced genes vs control treatment, fold change > 2.0, p-value < 0.01. Supplementary Table 11 - Vem + IFNg/TNFa vs IFNg/TNFa differentially expressed genes, FC > 1.5.

Supplementary Materials and Methods

Supplemental Figure S4. Akti-treated tumor-specific Pmel CD8+ T cell have reduced phosphorylation of Akt and substrates in presence of pharmacologic inhibition of Akt.

Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) results in complete regression of advanced cancer in some patients, but the efficacy of this potentially curative therapy may be limited by poor persistence of TIL after adoptive transfer. Pharmacologic inhibition of the serine/threonine kinase Akt has recently been shown to promote immunologic memory in virus-specific murine models, but whether this approach enhances features of memory (e.g., long-term persistence) in TIL that are characteristically exhausted and senescent is not established. Here, we show that pharmacologic inhibition of Akt enables expansion of TIL with the transcriptional, metabolic, and functional properties characteristic of memory T cells. Consequently, Akt inhibition results in enhanced persistence of TIL after adoptive transfer into an immunodeficient animal model and augments antitumor immunity of CD8 T cells in a mouse model of cell-based immunotherapy. Pharmacologic inhibition of Akt represents a novel immunometabolomic approach to enhance the persistence of antitumor T cells and improve the efficacy of cell-based immunotherapy for metastatic cancer. Cancer Res; 75(2); 296–305. ©2014 AACR.

Sarcomas are rare tumors of mesenchymal origin and comprise only around 1% of adult cancers. The abundance of sarcoma histiotypes, with distinct imaging characteristics, biology, clinical behavior and treatment strategy, result in a complex disease presentation, requiring management by multidisciplinary specialized sarcoma centers. Oncologic and musculoskeletal radiology guidelines provide minimal guidance and only fragmentary information on the indications of 18F-FDG PET/CT in sarcoma. Therefore, knowledge of various phenotypes with preference for bone and lymph node metastases or higher incidence of local and distant recurrence is essential to select the appropriate diagnostic imaging tests and its interpretation. Benign and malignant soft tissue and bone tumors often share common radiographic and metabolic imaging characteristics. In addition, metastases of various histiotypes might exhibit a spectrum of atypical imaging appearances. Therefore, imaging specialists need to be aware of these variants and associated pitfalls of sarcoma imaging.

An ambiguous pathologic report can present a clinical dilemma to the treating surgeon. We describe lesions ranging from the potentially benign to the likely malignant. Correctly identifying features associated with higher-risk lesions has proven challenging given the overall good prognosis and low rate of events. An appropriate treatment plan generally requires discussion between the surgeon and an experienced dermatopathologist. When clinically indicated, additional testing may be used to further support or refute a diagnosis of melanoma. The indications for these techniques, the data to support their use, and the strengths and weakness of each are reviewed.

PURPOSE Response to programmed cell death protein 1 (PD-1) blockade is often conceptualized as resulting from reinvigoration of tumor-infiltrating lymphocytes. However, recruited antitumor immunity from the periphery may also be an important contributor to response. A detailed assessment of the response dynamics of individual metastasis could provide insight to the systemic and local features that mediate response and resistance to immunotherapy. MATERIALS AND METHODS Patients with metastatic non–small-cell lung cancer (NSCLC) or mismatch repair deficiency (MMRD) carcinoma treated with PD-1 monotherapy were evaluated independently. Absolute and percent change of each target lesion were quantified at each computed tomography scan using RECIST. Patterns of progression were predefined as systemic or mixed and were correlated with clinical outcomes. RESULTS A total of 761 individual lesions from 214 patients with NSCLC and 290 lesions from 78 patients with MMRD carcinoma were examined. Individual target lesion responses aligned with best overall response of each patient (85% NSCLC and 93% MMRD lesions responded in patients with partial response/complete response). In responding patients, timing of response was uniform (73% NSCLC and 76% MMRD lesions responded synchronously), and deeper responses were associated with prolonged progression-free survival and overall survival. By contrast, at progression, mixed progression was common (45% of NSCLC and 53% of MMRD) and associated with improved survival compared with those who experienced systemic progression (NSCLC hazard ratio [HR], 0.58; P = .001; MMRD HR, 0.40; P = .07). Organ sites had differential responses, with lymph node and liver metastasis among the most and least responsive, respectively. CONCLUSION Temporal-spatial patterns of response across individual metastases tend to be uniform, favoring the role of peripheral, clonally directed antitumor immunity as a key mediator of response to PD-1 blockade. In contrast, progression is more heterogeneous, potentially revealing the clinical importance of local features and intertumoral heterogeneity.

Purpose/Objective(s) Preoperative radiation therapy (RT) is an integral component of local control in soft tissue sarcoma (STS), but the conventional 5-week treatment course is burdensome for patients (pts). We conducted a single-institution phase 2 study of 5-day dose-equivalent preoperative RT for high-risk primary STS, which demonstrated acceptable rates of wound complications and 2-year toxicity. Here, we present results with longer follow-up, including additional pts from an expansion cohort. Materials/Methods The initial cohort accrued between April 2016 and May 2018 and included 52 pts with histologically confirmed extremity or trunk STS planning to undergo preoperative RT followed by surgery. The primary endpoint of the initial cohort was the rate of grade ≥2 radiation morbidity (fibrosis, lymphedema, or joint stiffness) at 2-years. An expansion cohort opened in October 2018 to compare wound complication rates between preoperative RT alone versus chemoRT and has enrolled an additional 47 pts. Patients received 30 Gy (RT alone) or 25 Gy (chemoRT) over 5 daily fractions to the primary tumor with standard margins. Here we report on pts with primary localized STS who completed preoperative RT and surgery in the initial and expansion cohorts (N = 79; chemoRT excluded). We assessed disease outcomes (local control, distant metastasis, and survival rates) and toxicity (grade ≥2 fibrosis, lymphedema, or joint stiffness) after minimum 2-year follow-up (N = 52). Fibrosis and joint stiffness were graded using RTOG/EORTC criteria, and lymphedema by Stern's scale. We also updated the major wound complication rate (defined per established criteria) after minimum 1-year follow up (N = 60). Results Of the 52 pts with minimum 2-year follow-up, predominant histologic subtypes included undifferentiated pleomorphic sarcoma, spindle cell sarcoma or sarcoma NOS (N = 24), myxofibrosarcoma (N = 8), and myxoid liposarcoma (N = 12). Median tumor size was 6.9 cm, and 15 pts had tumors ≥10 cm. At a median follow-up of 3 years, the local recurrence, distant metastasis and all-cause mortality rates were 6.5% (3 of 46 evaluable pts), 20.8% (10 of 48 evaluable pts), and 21.2% (11 of 52). Two of 3 pts (66%) with a local recurrence had undergone R1 resections, compared to 9 of 46 (19.5%) overall. The rate of overall grade ≥2 radiation morbidity in this same group was 13.0% (fibrosis: 5 pts, joint stiffness: 5 pts, lymphedema: 2 pts). Major wound complications were observed in 16 out of 60 (26.7%) evaluable pts. Conclusion Longer follow-up of a phase 2 study of 5-day pre-operative RT for pts with extremity/trunk STS demonstrates excellent local control. Rates of radiation fibrosis, joint stiffness and lymphedema, as well as wound complications, remain acceptable. We have also developed a web-based, interactive user interface for data visualization, which can help providers identify and understand relationships between baseline characteristics and clinical outcomes in our study.

Purpose Given the diverse and aggressive nature of soft tissue sarcomas (STSs), a need exists for more-precise therapy. Patient-derived orthotopic xenografts (PDOXs) provide a unique platform for personalized treatment. Thus, identification of patient and treatment factors that predict PDOX establishment is important. This study assessed the feasibility of incorporating PDOXs into the clinical setting and identifying factors associated with PDOX establishment. Patients and Methods From May 2015 to May 2016, 107 patients with biopsy-proven or potential STS were enrolled. Tumor samples were obtained intraoperatively and orthotopically implanted into nude mice in the corresponding anatomic location. PDOXs were considered established after engraftment and serial passage. Factors associated with establishment were analyzed by logistic regression and time to establishment by time-to-event analysis. Results Only high-grade tumors established (32 of 72 [44.4%]). The establishment rate (ER) varied by neoadjuvant therapy and treatment response, with the highest ER among untreated high-grade tumors (26 of 42 [61.9%]). Tumors exposed to radiation preoperatively did not establish (zero of 11 [0%]), and tumors exposed to neoadjuvant chemotherapy had a lower ER (31.9%) than untreated tumors. Only STSs with minimal pathologic response to neoadjuvant treatment (≤ 30%) established a PDOX (six of 18 [33.3%]). Median establishment time was 54 days, which varied by neoadjuvant therapy but was not statistically significant ( P = .180). Conclusion To our knowledge, in the largest STS PDOX study to date, we demonstrate a 62% ER among untreated high-grade tumors with a median establishment time of 54 days. Neoadjuvant therapy, particularly radiation, and pathologic response to treatment were associated with a reduced rate of PDOX establishment.

Purpose: The purpose of this study was to evaluate 18F-FLT PET/CT as an early prognostic imaging biomarker of long-term overall survival (OS) and disease-specific survival (DSS) in soft tissue sarcoma (STS) patients treated with neoadjuvant therapy (NAT) and surgical resection. Methods: This is a 10-year follow up of a previous, single-center, single-arm, prospective clinical trial. Patients underwent 18F-FLT PET/CT prior to treatment (PET1) and after NAT (PET2). Post-treatment pathology specimens were assessed for tumor necrosis / fibrosis as well as Ki-67 and TK1 expression. Maximally selected cut-offs for PET and histopathologic factors were applied. Survival was calculated from the date of subject consent to the date of death or last follow-up. Results: The study population consisted of 26 patients who underwent PET1, 16/26 primary STS underwent PET2. Thirteen deaths occurred during a median follow up period of 104 months. In the overall cohort, OS was longer in patients with low versus high PET1 tumor SUVmax (dichotomized by SUVmax ≥ 8.5 vs. < 8.5; not yet reached vs. 49.7 months; P = 0.0064). DSS showed a trend toward significance (P = 0.096). In a sub-analysis of primary STS, DSS was significantly longer in patients with low versus high PET1 tumor SUVmax (dichotomized by SUVmax ≥ 8 vs < 8; P = 0.0034). There were no significant 18F-FLT PET response thresholds corresponding to DSS or OS following NAT at PET2. Conclusion: 18F-FLT PET may serve as prognostic baseline imaging biomarker for DSS in patients with primary STS.

Background: BO-112 is a double stranded synthetic RNA formulated with polyethyleneimine. By mimicking a viral infection, it mobilizes the immune system, including activation of dendritic cells, CD8 T-cell infiltration, induction of interferons, and enhancement of immunogenic cell death. Intratumoral (IT) BO-112 has been tested both alone and in combination with anti-PD-1 therapies in a phase I trial (NCT02828098), which showed an overall response rate (ORR) of 11% and disease control rate (DCR) of 46% in patients with multiple tumor types and a tolerable safety profile. While anti-PD1 therapies have shown promise in select subtypes of soft tissue sarcoma (STS), their overall efficacy in STS has been limited. We hypothesize that BO-112, in combination with radiotherapy (RT), may reverse resistance to anti-PD1 therapy in a subset of patients with STS. Methods: This is an exploratory phase I study of IT BO-112 in combination with nivolumab in patients with STS planning to undergo neoadjuvant RT (NCT04420975) and surgery. BO-112 at a dose of 1 mg will be administered intratumorally on days 1, 8 and 15; nivolumab 240 mg will be administered intravenously on days 8 and 22. Patients will receive 5 fractions of neoadjuvant RT between day 8 and 12, followed by surgical resection between days 26 and 50. Twenty patients with newly diagnosed high grade histologically confirmed STS of the extremity, trunk or retroperitoneum amenable for IT injection will be included. Allowed histological subtypes are undifferentiated pleomorphic sarcoma, myxofibrosarcoma, leiomyosarcoma, dedifferentiated liposarcoma and synovial sarcoma.The primary objective is to explore the safety of BO-112 in combination with nivolumab in patients undergoing preoperative RT. The study includes stopping rules based on the frequency of dose limiting toxicities. As an exploratory single arm pilot study results will be reported using purely descriptive statistics. Tumor and blood specimens collected at baseline, at each IT BO-112 injection, and surgery will allow evaluation of the dynamic changes in tumor immune infiltration, T cell receptor repertoire, and tumor necrosis. These dynamic changes, along with putative biomarkers, such as baseline tumor mutational load, copy number alterations, tumor immune composition, tumor and immune gene expression signatures, and PD-L1 expression, will be related to individual subject tumor responses. The 2-year rate of local recurrence and distant metastasis will also be assessed. This study began accrual in December 2020 and is open. Citation Format: Anusha Kalbasi, Fritz C. Eilber, Arun Singh, Bartosz Chmielowski, Nicholas Bernthal, Brooke Crawford, Joseph G. Crompton, Varand Ghazikhanian, Leanne Seeger, Kambiz Motamedi, Michael L. Douek, Carol Felix, Vincent Basehart, Helena Escuin-Ordinas, Marisol Quintero, Sonia Macia. A phase I study of intratumoral BO-112 and nivolumab for resectable soft tissue sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT221.

11546 Background: Surveillance imaging of patients with retroperitoneal liposarcoma (RP-LPS) following surgical resection is based on a projected risk of locoregional and distant recurrence. The duration of surveillance is not well defined as the long-term natural history of RP-LPS after treatment is poorly understood. We evaluate a cohort of RP-LPS patients—without evidence of disease 10 years following initial resection—to assess the long-term risk of recurrence and disease-specific survival (DSS). Methods: The prospectively maintained UCLA Sarcoma Database was used to identify RP-LPS patients who demonstrated 10-year progression-free survival (10yr-PFS) after initial diagnosis and treatment. Patients in the 10yr-PFS cohort were subsequently evaluated for recurrence and DSS. Time intervals start at date of initial surgical resection. Cox proportional hazards models were used to determine factors associated with recurrence and DSS. Results: From 1972-2010, 76 patients with RP-LPS had at least 10 years of follow-up. Of these, 37 (49%) demonstrated 10yr-PFS. Median follow-up was 15 years (range 10-35 years). Among the 10yr-PFS patients, 43% (16/37) developed a recurrence >10 years after the initial surgery, and 19% (7/37) died of disease. Neither long-term recurrence nor DSS were significantly associated with age, sex, tumor size, LPS subtype, surgical margin, or peri-operative treatment with radiation or chemotherapy (Table). Conclusions: Patients with primary RP-LPS treated with surgical resection +/- multimodality therapy have a long-term risk of recurrence and disease-specific death that is unacknowledged by current surveillance imaging guidelines. Among the patients with a 10yr-PFS, 43% developed a recurrence and 19% died of disease. These findings suggest a need for lifelong surveillance imaging in patients with RP-LPS.[Table: see text]

Background Inguinodynia, defined as pain lasting >3 months after inguinal hernia repair, remains the major complication of hernia operation. We sought to determine the effect of direct perineural infiltration on acute pain and inguinodynia after open inguinal hernia repair. Methods Patients who presented with an inguinal hernia at a university teaching hospital were evaluated prospectively and randomized to either (1) percutaneous ilioinguinal nerve block or (2) percutaneous ilioinguinal nerve block with additional perineural infiltration of the ilioinguinal, iliohypogastric, genitofemoral nerves. All patients in each group received a total of 12 mL of 0.5% bupivacaine. Self-reported faces of pain level (1–10), minutes to discharge from the recovery room, narcotic quantity consumed (oxycodone 5 mg/paracetamol 325 mg), days on narcotics, and incidence of inguinodynia at 3 months were all recorded. Results Ninety-two patients were randomized in the study. Patients who received perineural bupivacaine infiltration of nerves had less recovery room pain (1.3 vs 3.9, P P = .047) and consumed fewer narcotics (9.7 vs 15.1 doses, P = .010). The incidence of inguinodynia at 3 months was less in the treatment group (8.2% vs 27.9%, P = .013). Conclusion We have implemented a novel and inexpensive method of local nerve blockade that decreases pain immediately after operation and at 3 months postoperatively. Furthermore, our method leads to shorter recovery room stay and fewer narcotics after operation.

Liposarcoma is a mesenchymal malignancy that predominantly arises in the retroperitoneum, trunk, and extremities. Histologic subtypes of liposarcoma include well-differentiated/dedifferentiated, myxoid/round cell, and pleomorphic liposarcoma. Although liposarcoma is rare and can occur in almost any anatomic location, it is the most common soft tissue sarcoma in the retroperitoneum, and surgery remains the only potentially curative therapy. This review discusses liposarcoma pathogenesis, classification, clinical-diagnostic evaluation, treatment, and surveillance. The cornerstone of treatment is surgery, with the main therapeutic goals of improving survival, limiting local recurrence, maximizing function, and minimizing morbidity. Perioperative radiation therapy may be indicated in patients with large high-grade liposarcomas. Systemic treatment—whether traditional chemotherapy or molecularly targeted therapy—may benefit patients depending on their histologic subtype, location, and extent of disease. For the majority of patients, however, systemic treatment is not curative. Controversial issues in the management of liposarcoma, such as surgical margins and extent of resection, are also discussed. This review contains 2 figures, 5 tables and 39 references Key words: atypical lipomatous liposarcoma, liposarcoma, myxoid liposarcoma, pleomorphic liposarcoma, retroperitoneal sarcoma, soft tissue sarcoma, well-differentiated/dedifferentiated liposarcoma

Our laboratory pioneered patient-derived orthotopic xenograft (PDOX) mouse models using surgical orthotopic implantation (SOI). PDOX models are patient-like, in contrast to the ectopic subcutaneous-transplant cancer models. In the present study, we demonstrate that an undifferentiated pleomorphic soft-tissue sarcoma (UPS-STS) PDOX model acquired bright RFP-expressing stroma through one passage in red fluorescent protein (RFP) transgenic mice, which upon passage to non-colored nude mice was non-invasively imageable. A PDOX nude mouse model of UPS-STS was established in the biceps femoris of nude mice. After the tumors grew to a diameter of 10 mm, the tumors were subsequently passaged to RFP transgenic mice, and after tumor growth were then passaged to non-transgenic nude mice. Tumors were divided into small fragments and transplanted in the biceps femoris at each passage. The OV100 Small Animal Fluorescence Imaging System and FV1000 laser scanning confocal microscope were used to image RFP fluorescence in the UPS-STS PDOX models. UPS-STS PDOX tumors, previously grown in RFP transgenic nude mice for only one passage, had very bright fluorescence and after passage to non-transgenic nude mice maintained the bright fluorescence and were non-invasively imageable. FV1000 confocal imaging revealed diffusely distributed bright RFP stromal cells in the PDOX tumor, both in RFP transgenic mice and after passage to non-transgenic mice. These results demonstrate a powerful method to make the PDOX UPS-STS model brightly fluorescent for non-invasive imaging, as well as for confocal microscopy of individual stromal cells associated with the tumor. The RFP-labeled UPS PDOX has the potential to rapidly screen for novel effective agents for individual patients, including stroma-targeting drugs, whereby the stromal cells are a visual target. J. Cell. Biochem. 118: 361-365, 2017. © 2016 Wiley Periodicals, Inc.

Long-term survival and antitumor immunity of adoptively transferred CD8(+) T cells is dependent on their metabolic fitness, but approaches to isolate therapeutic T cells based on metabolic features are not well established. Here we utilized a lipophilic cationic dye tetramethylrhodamine methyl ester (TMRM) to identify and isolate metabolically robust T cells based on their mitochondrial membrane potential (ΔΨm). Comprehensive metabolomic and gene expression profiling demonstrated global features of improved metabolic fitness in low-ΔΨm-sorted CD8(+) T cells. Transfer of these low-ΔΨm T cells was associated with superior long-term in vivo persistence and an enhanced capacity to eradicate established tumors compared with high-ΔΨm cells. Use of ΔΨm-based sorting to enrich for cells with superior metabolic features was observed in CD8(+), CD4(+) T cell subsets, and long-term hematopoietic stem cells. This metabolism-based approach to cell selection may be broadly applicable to therapies involving the transfer of HSC or lymphocytes for the treatment of viral-associated illnesses and cancer.

Although immunosuppression has been a key component to the success of solid-organ transplantation, the morbidity associated with long-term immunosuppression remains a substantial burden, particularly as recipients of transplants live longer. Indeed, malignancy is one of the most common reasons for mortality following transplantation and the most common of these cancers are cutaneous in origin. Recently, the incidence of these malignancies has been on the rise, partly due to the fact that recipients of these transplants are living longer as a result of improvements in surgical technique, immunosuppression and perioperative management. Although there have been initiatives to increase awareness of cutaneous malignancies following transplantation, such programs are not standardized and there continues to be gaps in skin cancer education and post-operative surveillance. This review provides an update on the epidemiology, risk factors, clinical management, prevention and surveillance of cutaneous malignancies.

The new edition of the American Joint Committee on Cancer staging system for melanoma builds on the foundation of prior editions but has several important improvements. The availability of regional nodal staging using sentinel lymph node biopsy (with subsequent follow-up) has resulted in more accurate prognostication for patients and clinicians. This facilitates identification of those at higher risk for recurrence, and allows for the appropriate selection of patients for new adjuvant therapy and clinical trials. Although more complex than previous editions, the eighth edition will provide granularity to outcome analysis based on more precise risk stratification.

Sarcomas of soft tissue and bone are mesenchymal malignancies that can arise in any anatomic location, most commonly the extremity, retroperitoneum, and trunk. Even for lower grade histologic subtypes, local recurrence can cause significant morbidity and even disease-related death. Although surgery remains the cornerstone of local control, perioperative radiation and systemic therapy are often important adjuvants. This review will summarize the current therapeutic approaches for local control of soft tissue and bone sarcomas.

Adoptive immunotherapies using T cells genetically redirected with a chimeric antigen receptor (CAR) or T cell receptor (TCR) are entering mainstream clinical practice. Despite encouraging results, some patients do not respond to current therapies. In part, this phenomenon has been associated with infusion of reduced numbers of early memory T cells. Herein, we report that AKT signaling inhibition is compatible with CAR and TCR retroviral transduction of human T cells while promoting a CD62L-expressing central memory phenotype. Critically, this intervention did not compromise cell yield. Mechanistically, disruption of AKT signaling preserved MAPK activation and promoted the intranuclear localization of FOXO1, a transcriptional regulator of T cell memory. Consequently, AKT signaling inhibition synchronized the transcriptional profile for FOXO1-dependent target genes across multiple donors. Expression of an AKT-resistant FOXO1 mutant phenocopied the influence of AKT signaling inhibition, while addition of AKT signaling inhibition to T cells expressing mutant FOXO1 failed to further augment the frequency of CD62L-expressing cells. Finally, treatment of established B cell acute lymphoblastic leukemia was superior using anti-CD19 CAR-modified T cells transduced and expanded in the presence of an AKT inhibitor compared with conventionally grown T cells. Thus, inhibition of signaling along the PI3K/AKT axis represents a generalizable strategy to generate large numbers of receptor-modified T cells with an early memory phenotype and superior antitumor efficacy.

To better elucidate epigenetic mechanisms that correlate with the dynamic gene expression program observed upon T-cell differentiation, we investigated the genomic landscape of histone modifications in naive and memory CD8(+) T cells. Using a ChIP-Seq approach coupled with global gene expression profiling, we generated genome-wide histone H3 lysine 4 (H3K4me3) and H3 lysine 27 (H3K27me3) trimethylation maps in naive, T memory stem cells, central memory cells, and effector memory cells in order to gain insight into how histone architecture is remodeled during T cell differentiation. We show that H3K4me3 histone modifications are associated with activation of genes, while H3K27me3 is negatively correlated with gene expression at canonical loci and enhancers associated with T-cell metabolism, effector function, and memory. Our results also reveal histone modifications and gene expression signatures that distinguish the recently identified T memory stem cells from other CD8(+) T-cell subsets. Taken together, our results suggest that CD8(+) lymphocytes undergo chromatin remodeling in a progressive fashion. These findings have major implications for our understanding of peripheral T-cell ontogeny and the formation of immunological memory.

Highlights • Nasopharyngeal mucosal melanoma is a rare pathology with an unclear etiology and oftentimes obscure clinical presentation. • We present a report of a lady who had a complete response to systemic treatment of metastatic melanoma of unknown origin. • Six years later, a diagnosis of primary nasopharyngeal melanoma was made after an extensive work-up for recurrent symptoms of severe right-sided epistaxis and hearing loss. • Surgical resection was performed followed by radiation therapy. The patient has since been without evidence of recurrent or metastatic disease and resolution of bleeding., Introduction Primary nasopharyngeal melanoma is an exceedingly rare pathology with unclear etiology and oftentimes obscure clinical presentation. Despite improved diagnostic capabilities, these lesions are often diagnosed at an advanced stage and associated prognosis is poor, partly due to high rates of recurrences and metastasis. Presentation of case A 74-year-old woman was diagnosed with metastatic melanoma to the liver, of unknown primary. Just prior to the time of diagnosis, she experienced several episodes of severe epistaxis which she managed conservatively. Her symptoms eventually subsided without further medical evaluation. The patient was initially treated with interleukin-2 (IL-2) for her advanced disease, but her cancer progressed. She was then enrolled in a protocol for percutaneous hepatic perfusion (PHP) with melphalan and had complete radiographic resolution of disease, yet her nosebleeds recurred and persisted despite conservative measures. Six years after her initial diagnosis, a nasopharyngoscopy demonstrated a pigmented lesion in the posterior nasopharynx. Surgical resection was performed (pathology consistent with mucosal melanoma) followed by radiation therapy. She has since had complete resolution of bleeding and shows no evidence of cancer. Discussion To our knowledge, this is the first report of a diagnosis of primary nasopharyngeal melanoma 6-years following complete remission of metastatic disease. Surgery remains the primary treatment for disease and symptom control in this setting. Conclusion Timely diagnosis of nasopharyngeal melanomas remains challenging. Thorough clinical evaluations should be performed in such patients, and attention should be paid to recurrent and persistent symptoms, such as epistaxis and hearing loss. This may allow for earlier detection of primary disease.

Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) results in complete regression of advanced cancer in some patients, but the efficacy of this potentially curative therapy may be limited by poor persistence of TIL after adoptive transfer. Pharmacologic inhibition of the serine/threonine kinase Akt has recently been shown to promote immunologic memory in virus-specific murine models, but whether this approach enhances features of memory (e.g., long-term persistence) in TIL that are characteristically exhausted and senescent is not established. Here, we show that pharmacologic inhibition of Akt enables expansion of TIL with the transcriptional, metabolic, and functional properties characteristic of memory T cells. Consequently, Akt inhibition results in enhanced persistence of TIL after adoptive transfer into an immunodeficient animal model and augments antitumor immunity of CD8 T cells in a mouse model of cell-based immunotherapy. Pharmacologic inhibition of Akt represents a novel immunometabolomic approach to enhance the persistence of antitumor T cells and improve the efficacy of cell-based immunotherapy for metastatic cancer. Cancer Res; 75(2); 296–305. ©2014 AACR.

Palmer et al. find that Cish, a member of the SOCS family, is induced by TCR stimulation in CD8+ T cells and inhibits their functional avidity against tumor. The authors uncover a novel mechanism of suppression for a SOCS member., Improving the functional avidity of effector T cells is critical in overcoming inhibitory factors within the tumor microenvironment and eliciting tumor regression. We have found that Cish, a member of the suppressor of cytokine signaling (SOCS) family, is induced by TCR stimulation in CD8+ T cells and inhibits their functional avidity against tumors. Genetic deletion of Cish in CD8+ T cells enhances their expansion, functional avidity, and cytokine polyfunctionality, resulting in pronounced and durable regression of established tumors. Although Cish is commonly thought to block STAT5 activation, we found that the primary molecular basis of Cish suppression is through inhibition of TCR signaling. Cish physically interacts with the TCR intermediate PLC-γ1, targeting it for proteasomal degradation after TCR stimulation. These findings establish a novel targetable interaction that regulates the functional avidity of tumor-specific CD8+ T cells and can be manipulated to improve adoptive cancer immunotherapy.

BACKGROUND: Here we describe the Systematically Tabulated Outcomes Research Matrix (STORM) method to generate research questions from pre-existing databases with the aim of improving patient outcomes. MATERIALS AND METHODS: STORM can be applied to a database by tabulating its variables into a matrix of independent variables (y-axis) and dependent variables (x-axis) and then applying each unique pairing of an independent and dependent variable to a patient population to generate potentially meaningful research questions. RESULTS: To demonstrate this methodology and establish proof-of-principle, STORM was applied on a small scale to the National Trauma Data Bank and generated at least seven clinically meaningful research questions. CONCLUSION: When coupled with rigorous clinical judgment, the STORM approach complements the traditional method of hypothesis formation and can be generalized to outcomes research using registry databases across different medical specialties. Language: en

Naive CD8+ T cells rely upon oxidation of fatty acids as a primary source of energy. After antigen encounter, T cells shift to a glycolytic metabolism to sustain effector function. It is unclear, however, whether changes in glucose metabolism ultimately influence the ability of activated T cells to become long-lived memory cells. We used a fluorescent glucose analog, 2-NBDG, to quantify glucose uptake in activated CD8+ T cells. We found that cells exhibiting limited glucose incorporation had a molecular profile characteristic of memory precursor cells and an increased capacity to enter the memory pool compared with cells taking up high amounts of glucose. Accordingly, enforcing glycolytic metabolism by overexpressing the glycolytic enzyme phosphoglycerate mutase-1 severely impaired the ability of CD8+ T cells to form long-term memory. Conversely, activation of CD8+ T cells in the presence of an inhibitor of glycolysis, 2-deoxyglucose, enhanced the generation of memory cells and antitumor functionality. Our data indicate that augmenting glycolytic flux drives CD8+ T cells toward a terminally differentiated state, while its inhibition preserves the formation of long-lived memory CD8+ T cells. These results have important implications for improving the efficacy of T cell–based therapies against chronic infectious diseases and cancer.

Engineering CD8⁺ T cells to deliver interleukin 12 (IL-12) to the tumor site can lead to striking improvements in the ability of adoptively transferred T cells to induce the regression of established murine cancers. We have recently shown that IL-12 triggers an acute inflammatory environment that reverses dysfunctional antigen presentation by myeloid-derived cells within tumors and leads to an increase in the infiltration of adoptively transferred antigen-specific CD8⁺ T cells. Here, we find that local delivery of IL-12 increased the expression of Fas within tumor-infiltrating macrophages, dendritic cells, and myeloid-derived suppressor cells (MDSC), and that these changes were abrogated in mice deficient in IL-12-receptor signaling. Importantly, upregulation of Fas in host mice played a critical role in the proliferation and antitumor activity of adoptively transferred IL-12-modified CD8⁺ T cells. We also observed higher percentages of myeloid-derived cell populations within tumors in Fas-deficient mice, indicating that tumor stromal destruction was dependent on the Fas death receptor. Taken together, these results describe the likely requirement for costimulatory reverse signaling through Fasl on T cells that successfully infiltrate tumors, a mechanism triggered by the induction of Fas expression on myeloid-derived cells by IL-12 and the subsequent collapse of the tumor stroma.

Diverse autoimmune and allergic diseases are associated with polymorphisms in a locus encoding the transcription factor BACH2; here, BACH2 is shown to be a broad regulator of immune activation that stabilizes the differentiation of Treg cells by repressing commitment of CD4+ T cells to alternate cell fates. Polymorphisms within a locus encoding the transcription factor BACH2 are associated with a number of allergic and autoimmune diseases including asthma, multiple sclerosis, Crohn's disease, coeliac disease and type 1 diabetes. This paper identifies a mechanism by which BACH2 might contribute to autoimmunity. Roychoudhuri et al. show how BACH2 limits autoimmunity by repressing alternative cell fates through the stabilization of the differentiation of regulatory T cells. These findings suggest a role for BACH2 as a regulator of CD4+ T-cell differentiation, preventing inflammatory disease by controlling the balance between tolerance and immunity. Through their functional diversification, distinct lineages of CD4+ T cells can act to either drive or constrain immune-mediated pathology. Transcription factors are critical in the generation of cellular diversity, and negative regulators antagonistic to alternate fates often act in conjunction with positive regulators to stabilize lineage commitment1. Genetic polymorphisms within a single locus encoding the transcription factor BACH2 are associated with numerous autoimmune and allergic diseases including asthma2, Crohn’s disease3,4, coeliac disease5, vitiligo6, multiple sclerosis7 and type 1 diabetes8. Although these associations point to a shared mechanism underlying susceptibility to diverse immune-mediated diseases, a function for BACH2 in the maintenance of immune homeostasis has not been established. Here, by studying mice in which the Bach2 gene is disrupted, we define BACH2 as a broad regulator of immune activation that stabilizes immunoregulatory capacity while repressing the differentiation programs of multiple effector lineages in CD4+ T cells. BACH2 was required for efficient formation of regulatory (Treg) cells and consequently for suppression of lethal inflammation in a manner that was Treg-cell-dependent. Assessment of the genome-wide function of BACH2, however, revealed that it represses genes associated with effector cell differentiation. Consequently, its absence during Treg polarization resulted in inappropriate diversion to effector lineages. In addition, BACH2 constrained full effector differentiation within TH1, TH2 and TH17 cell lineages. These findings identify BACH2 as a key regulator of CD4+ T-cell differentiation that prevents inflammatory disease by controlling the balance between tolerance and immunity.

// Elizabeth Shurell 1, * , Arun S. Singh 2, 7, * , Joseph G. Crompton 1 , Sarah Jensen 2 , Yunfeng Li 3 , Sarah Dry 3, 7 , Scott Nelson 3, 7 , Bartosz Chmielowski 2, 7 , Nicholas Bernthal 4, 7 , Noah Federman 2, 7 , Paul Tumeh 5, 7 , Fritz C. Eilber 1, 6, 7 1 Division of Surgical Oncology, Department of Surgery, University of California, Los Angeles, CA 90095, USA 2 Department of Hematology/Oncology, University of California, Los Angeles, CA 90095, USA 3 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA 4 Department of Orthopaedic Surgery, University of California, Los Angeles, CA 90095, USA 5 Department of Dermatology, University of California, Los Angeles, CA 90095, USA 6 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA 7 UCLA JCCC Sarcoma Program, University of California, Los Angeles, CA 90095, USA * indicates co-first authors Correspondence to: Fritz C. Eilber, email: fceilber@mednet.ucla.edu Keywords: immune microenvironment, MPNST, PD-L1, CD8, sarcoma Received: June 29, 2016 Accepted: August 16, 2016 Published: August 31, 2016 ABSTRACT Background: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma with few treatment options. Tumor immune state has not been characterized in MPNST, and is important in determining response to immune checkpoint blockade. Our aim was to evaluate the expression of programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), and presence of CD8+ tumor infiltrating lymphocytes (TILs) in MPNST, and correlate these findings with clinical behavior and outcome. Results: PD-L1 staining of at least 1% was seen in 0/20 nerves, 2/68 benign lesions and 9/53 MPNST. Two of 68 benign lesions and 7/53 (13%) MPNST had at least 5% PD-L1 staining. CD8 staining of at least 5% was seen in 1/20 (5%) nerves, 45/68 (66%) benign lesions and 30/53 (57%) MPNST. PD-L1 was statistically more prevalent in MPNST than both nerves and benign lesions (p=0.049 and p=0.008, respectively). Expression of PD-1 was absent in all tissue specimens. There was no correlation of PD-L1 or CD8 expression with disease state (primary versus metastatic) or patient survival. Methods: A comprehensive PNST tissue microarray was created from 141 surgical specimens including primary, recurrent, and metastatic MPNST (n=53), neurofibromas (n=57), schwannoma (n=11), and normal nerve (n=20). Cores were stained in triplicate for PD-L1, PD-1, and CD8, and expression compared between tumor types. These data were then examined for survival correlates in 35 patients with primary MPNST. Conclusions: MPNST is characterized by low PD-L1 and absent PD-1 expression with significant CD8+ TIL presence. MPNST immune microenvironment does not correlate with patient outcome.

// Elizabeth Shurell 1, * , Maria E. Vergara-Lluri 2, * , Yunfeng Li 3 , Joseph G. Crompton 1 , Arun Singh 4 , Nicholas Bernthal 5 , Hong Wu 3 , Fritz C. Eilber 1 , Sarah M. Dry 2 1 Division of Surgical Oncology, University of California, Los Angeles, CA 90095, USA 2 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA 3 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA 4 Department of Hematology/Oncology, University of California, Los Angeles, CA 90095, USA 5 Department of Orthopaedic Surgery, University of California, Los Angeles, CA 90095, USA * Co-first author Correspondence to: Fritz C. Eilber, email: fceilber@mednet.ucla.edu Keywords: NY-ESO-1, sarcoma, MPNST, liposarcoma, immunotherapy Received: July 28, 2016 Accepted: September 09, 2016 Published: September 17, 2016 ABSTRACT Background: Immunotherapy targeting cancer-testis antigen NY-ESO-1 shows promise for tumors with poor response to chemoradiation. Malignant peripheral nerve sheath tumors (MPNSTs) and liposarcomas (LPS) are chemoresistant and have few effective treatment options. Materials Methods: Using a comprehensive tissue microarray (TMA) of both benign and malignant tumors in primary, recurrent, and metastatic samples, we examined NY-ESO-1 expression in peripheral nerve sheath tumor (PNST) and adipocytic tumors. The PNST TMA included 42 MPNSTs (spontaneous n = 26, NF1-associated n = 16), 35 neurofibromas (spontaneous n = 22, NF-1 associated n = 13), 11 schwannomas, and 18 normal nerves. The LPS TMA included 48 well-differentiated/dedifferentiated (WD/DD) LPS, 13 myxoid/round cell LPS, 3 pleomorphic LPS, 8 lipomas, 1 myelolipoma, and 3 normal adipocytic tissue samples. Stained in triplicate, NY-ESO-1 intensity and density were scored. Results: NY-ESO-1 expression was exclusive to malignant tumors. 100% of myxoid/round cell LPS demonstrated NY-ESO-1 expression, while only 6% of WD/DD LPS showed protein expression, one of which was WD LPS. Of MPNST, 4/26 (15%) spontaneous and 2/16 (12%) NF1-associated MPNSTs demonstrated NY-ESO-1 expression. Strong NY-ESO-1 expression was observed in myxoid/round cell and dedifferentiated LPS, and MPNST in primary, neoadjuvant, and metastatic settings. Conclusions: We found higher prevalence of NY-ESO-1 expression in MPNSTs than previously reported, highlighting a subset of MPNST patients who may benefit from immunotherapy. This study expands our understanding of NY-ESO-1 in WD/DD LPS and is the first demonstration of staining in a WD LPS and metastatic/recurrent myxoid/round cell LPS. These results suggest immunotherapy targeting NY-ESO-1 may benefit patients with aggressive tumors resistant to conventional therapy.

Pharmacologic inhibitors of the serine/threonine kinase Akt, initially aimed at deranged oncogenic pathways in tumors, have recently been shown to act as immunomodulators that markedly enhance the antitumor properties of T cells. Repurposing Akt inhibitors to improve antitumor immunity may be viewed as a manifestation of a larger paradigmatic shift in which hallmark characteristics of cancer (e.g., immune evasion), rather than merely causal features (e.g., somatic mutations) can be exploited for therapeutic benefit.

BACKGROUND/PURPOSE: The mechanism of injury (MOI) may serve as a useful adjunct to injury scoring systems in pediatric trauma outcomes research. The objective is to determine the independent effect of MOI on case fatality and functional outcomes in pediatric trauma patients. METHODS: Retrospective review of pediatric patients ages 2 to 18 years in the National Trauma Data Bank from 2002 through 2006 was done. Mechanism of injury was classified by the International Classification of Diseases, Ninth Revision, E codes. The main outcome measures were mortality, discharge disposition (home vs rehabilitation setting), and functional impairment at hospital discharge. Multiple logistic regression was used to adjust for injury severity (using the Injury Severity Score and the presence of shock upon admission in the emergency department), age, sex, and severe head or extremity injury. RESULTS: Thirty-five thousand ninety-seven pediatric patients in the National Trauma Data Bank met inclusion criteria. Each MOI had differences in the adjusted odds of death or functional disabilities as compared with the reference group (fall). The MOI with the greatest risk of death was gunshot wounds (odds ratio [OR], 3.52; 95% confidence interval [CI], 2.23-5.54 95). Pediatric pedestrians struck by a motor vehicle have the highest risk of locomotion (OR, 3.30; 95% CI, 2.89-3.77) and expression (OR, 1.65; 95% CI, 1.22-2.23) disabilities. CONCLUSION: Mechanism of injury is a significant predictor of clinical and functional outcomes at discharge for equivalently injured patients. These findings have implications for injury prevention, staging, and prognosis of traumatic injury and posttreatment planning. Language: en

Basic science research suggests that sex hormones affect survival after traumatic shock. This study sought to determine the independent effect of gender on mortality among trauma patients in different hormone-related age groups.Review of severely injured trauma patients with shock included in the National Trauma Databank. Patients were stratified into three groups on the basis of likely hormonal status: prehormonal (age, 0-12 years), hormonal (age,13-64 years), and posthormonal (age, ≥ 65 years). Multiple logistic regression was used to analyze the independent effect of gender on mortality in each group, adjusting for anatomic and physiologic injury severity.A total of 48,394 patients met our inclusion criteria (Injury Severity Score ≥ 16 and systolic blood pressure90 mm Hg). Crude mortality was higher (p0.05) for males in all categories: prehormonal = 29% for males (n = 3,553) versus 24% for females (n = 1,831); hormonal = 34% for males (n = 26,778) versus 30% for females (n = 8,677) and posthormonal = 36% for males (n = 4,280) versus 31% for females (n = 3,275). After adjusting for covariates, women in the hormonally active group had a 14% decreased odds of death (0.86 [95% CI, 0.76-0.93]) compared with men. Females did not exhibit this survival advantage in the prehormonal (odds of death = 0.92 [0.74-1.14]) or posthormonal (odds of death = 0.90 [0.76-1.05]) groups.Females aged between 13 and 64 years exhibit significantly lower mortality than males after trauma-associated shock. This outcome difference is lost at the extremes of age (preadolescent children and individuals aged ≥ 65 years) where the effects of sex hormones are absent or diminished. These findings suggest that hormonal differences play a role in the gender-based outcome disparities after traumatic shock.

A dense sea fog episode that occurred near the coastal city of Qingdao in the Shandong Peninsula of China on 1 August 2003 is investigated by using all of the available observational data and high-resolution modeling results from the Regional Atmospheric Modeling System (RAMS). This fog event reduced the horizontal visibility to be less than 60 m in some locations and caused several traffic accidents locally. In this paper, all of the available observational data, including visible satellite imagery of Geostationary Operational Environmental Satellite (GOES)-9 and MODerate-resolution Imaging Spectroradiometer (MODIS), objectively reanalyzed Final Analysis (FNL) data issued by the National Centers for Environmental Prediction (NCEP), sounding data at the Qingdao and Dalian stations, and the latest 4.4 version of the RAMS model, were employed to study this sea fog case. We begin with the analyses of the environmental conditions of the sea fog event, including the large-scale conditions, the difference between T 2m (air temperature at 2 m altitude) and sea surface temperature (SST), and the atmospheric sounding profiles of the two stations. The characteristics of this sea fog event was documented by using visible satellite imagery of GOES-9 and MODIS. In order to better understand the fog formation mechanism, a high-resolution RAMS model of dimensions 4 km × 4 km was designed, which was initialized and validated by FNL data. A 54-h modeling period that started from 18 UTC 31 July 2003 reproduced the main characteristics of this sea fog event. The simulated lower visibility area agreed well with the sea fog area identified from the satellite imagery. It is shown that advection cooling effect plays a significant role in the fog formation.

Background The Revised Trauma Score (RTS) is commonly used to assess physiologic injury; however its use is limited by missing data. This study compares different parameters of physiologic injury assessment in their ability to predict mortality after trauma. Methods Adult patients in the National Trauma Data Bank (NTDB version 7.0) were analyzed, and the following physiologic injury parameters were compared: RTS, systolic blood pressure (SBP), shock (SBP ≤ 90 mm Hg), Glasgow coma scale-total (GCS-T), and GCS-motor (GCS-M). Areas under the receiver-operating characteristic curves (AUROC) were calculated for unadjusted and multivariate regression models to predict mortality after trauma. Results There were 1,484,648 patients who met inclusion criteria. In unadjusted analyses, RTS had the highest proportion of missing data (21%) and was highly predictive of mortality (AUROC = 0.85). SBP and shock had a much lower AUROC of 0.67 and 0.66, respectively, but had many fewer missing cases. The combination parameters of GCS-M with SBP or GCS-M with shock showed AUROC comparable to RTS (0.85) with approximately 80,000 fewer missing cases. Conclusion The discriminatory power of RTS is significantly better than SBP, shock, or GCS alone. Given the limitation of missing data associated with RTS, the combination of SBP and GCS-M is a more reliable and equally effective method of assessing physiologic injury severity in studying trauma outcomes.

In the original article the middle initial of Nicholas D. Klemen was inadvertently omitted. On the first page of the original article, under the heading A Novel Way to Fight Cancer, there was an error in the third sentence. The corrected text is as follows: For example, the presence of T cells within tumors of colorectal origin can be a superior predictor of patient survival compared with the standard histopathologic methods currently used to stage colorectal cancer.6,7.

Background Studies of sexual dimorphism in trauma outcomes suggest that women have a survival advantage compared to equivalently injured men. It is unknown if this gender disparity is mediated by potentially life-threatening complications. Objective To determine (1) if there is a sex-based differences in the odds of developing inpatient complications after trauma, and (2) if are these complications associated with death among trauma patients. Methods Review of adult trauma patients admitted to hospitals in the National Trauma Data Bank that report complications. Patient and injury severity covariates were adjusted using multiple logistic regression and the independent effect of sex on developing complications and associated mortality was determined. Results A total of 681,730 adult patients met the inclusion criteria of hospital admission ≥3 days. Women demonstrated a 21% lower adjusted risk of death compared to males (OR 0.79, 95% CI 0.76–0.83). Females had decreased adjusted odds of developing life-threatening complications including pneumonia, acute respiratory distress syndrome, acute renal failure and pulmonary embolism. However, when compared to males with life-threatening complications, females with complications were found to be at greater risk of dying. Conclusion This study demonstrates that women are less likely than men to develop inpatient complications, suggesting that the survival advantage among women after traumatic injury may involve a reduced susceptibility to developing life-threatening complications.

The immune system has a powerful ability to recognize and kill cancer cells, but its function is often suppressed within tumors, preventing clearance of disease. Functionally diverse innate and adaptive cellular lineages either drive or constrain immune reactions within tumors. The transcription factor (TF) BACH2 regulates the differentiation of multiple innate and adaptive cellular lineages, but its role in controlling tumor immunity has not been elucidated. Here, we demonstrate that BACH2 is required to establish immunosuppression within tumors. Tumor growth was markedly impaired in Bach2-deficient mice and coincided with intratumoral activation of both innate and adaptive immunity. However, augmented tumor clearance in the absence of Bach2 was dependent upon the adaptive immune system. Analysis of tumor-infiltrating lymphocytes from Bach2-deficient mice revealed high frequencies of rapidly proliferating effector CD4+ and CD8+ T cells that expressed the inflammatory cytokine IFN-γ. Effector T cell activation coincided with a reduction in the frequency of intratumoral Foxp3+ Tregs. Mechanistically, BACH2 promoted tumor immunosuppression through Treg-mediated inhibition of intratumoral CD8+ T cells and IFN-γ. These findings demonstrate that BACH2 is a key component of the molecular program of tumor immunosuppression and identify therapeutic targets for the reversal of immunosuppression in cancer.

Both targeted inhibition of oncogenic driver mutations and immune-based therapies show efficacy in treatment of patients with metastatic cancer, but responses can be either short lived or incompletely effective. Oncogene inhibition can augment the efficacy of immune-based therapy, but mechanisms by which these two interventions might cooperate are incompletely resolved. Using a novel transplantable BRAFV600E-mutant murine melanoma model (SB-3123), we explored potential mechanisms of synergy between the selective BRAFV600E inhibitor vemurafenib and adoptive cell transfer (ACT)–based immunotherapy. We found that vemurafenib cooperated with ACT to delay melanoma progression without significantly affecting tumor infiltration or effector function of endogenous or adoptively transferred CD8+ T cells, as previously observed. Instead, we found that the T-cell cytokines IFNγ and TNFα synergized with vemurafenib to induce cell-cycle arrest of tumor cells in vitro. This combinatorial effect was recapitulated in human melanoma–derived cell lines and was restricted to cancers bearing a BRAFV600E mutation. Molecular profiling of treated SB-3123 indicated that the provision of vemurafenib promoted the sensitization of SB-3123 to the antiproliferative effects of T-cell effector cytokines. The unexpected finding that immune cytokines synergize with oncogene inhibitors to induce growth arrest has major implications for understanding cancer biology at the intersection of oncogenic and immune signaling and provides a basis for design of combinatorial therapeutic approaches for patients with metastatic cancer. Cancer Immunol Res; 3(1); 37–47. ©2014 AACR. See related commentary by Riddell, p. 23

In two studies published in this issue of Cell Stem Cell, Nishimura et al. (2013) and Vizcardo et al. (2013) reprogram mature, antigen-specific cytotoxic T cells into induced pluripotent stem cells (iPSCs). The antigen-specific iPSCs can be redifferentiated into "rejuvenated" proliferative T cells and have broad applications for adoptive immunotherapy.