Safety and short-term outcomes of esophagectomy after neoadjuvant immunotherapy combined with chemotherapy or chemoradiotherapy for locally advanced esophageal squamous cell cancer: analysis of two phase-II clinical trials.

Background: Preoperative chemotherapy (CT) or chemoradiotherapy (CRT) show survival benefits in patients with locally advanced esophageal squamous cell carcinoma (ESCC); however, ESCC patients still have a dismal prognosis. We conducted two phase-II, single-armed clinical trials to assess the potential benefits, efficacy, feasibility, and safety of esophagectomy after combining preoperative CT or CRT and neoadjuvant programmed cell death protein 1 (PD-1) inhibitors in the treatment of ESCC. Methods: Patients were included with histologically confirmed ESCC (clinical stage II-IVA according to the American Joint Committee on Cancer 8th staging system) from two phase-II, single-arm trials (NCT04506138 and NCT03940001). Patients underwent two doses of intravenous PD-1 inhibitor (either camrelizumab or sintilimab) every 3 weeks, combined with two cycles of either CT or CRT. The primary endpoint of the study was the safety and short-term outcomes of esophagectomy as measured by the risk of developing complications within 30 days, after the combination of preoperative PD-1 inhibitor and CT or CRT Secondary endpoint was to evaluate the pCR rates (pT0N0), primary tumor pCR rates (pT0), operation time, postoperative stay, and 30-day mortality rate between both groups. Results between both groups were compared using a multivariable log-binomial regression model to obtain the adjusted relative risk ratios (RRs). Results: Between May 2019 and June 2022, 55 patients were included. All patients completed neoadjuvant therapy. Age, sex, performance status, clinical stage, histologic subtype, procedure type, operative time, and blood loss volume were similar between the two groups. The primary tumor pCR rates were 52.9% in the nICRT group and 21.6% in the nICT group (P=0.03), while the postoperative pCR rates were 41.2% in the nICRT group and 21.6% in the nICT group (P=0.19). The minimally invasive surgery rates were 89.2% (33/37) in the nICT group and 94.1% (16/17) in the nICRT group. The risk of developing pulmonary, anastomotic, or other complications were similar between the two groups. Conclusions: Esophagectomy was safe after the addition of the PD-1 inhibitor to preoperative CT or CRT in ESCC neoadjuvant therapies. Follow-up and the exploratory endpoints, including biomarkers analyses, are ongoing.

Integrative genomic and transcriptomic profiling of pulmonary sarcomatoid carcinoma identifies molecular subtypes associated with distinct immune features and clinical outcomes.

Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive subtype of non-small cell lung cancer (NSCLC), characterized by the presence of epithelial and sarcoma-like components. The molecular and immune landscape of PSC has not been well defined. Methods: Multiomics profiling of 21 pairs of PSCs with matched normal lung tissues was performed through targeted high-depth DNA panel, whole-exome, and RNA sequencing. We describe molecular and immune features that define subgroups of PSC with disparate genomic and immunogenic features as well as distinct clinical outcomes. Results: In total, 27 canonical cancer gene mutations were identified, with TP53 the most frequently mutated gene, followed by KRAS. Interestingly, most TP53 and KRAS mutations were earlier genomic events mapped to the trunks of the tumors, suggesting branching evolution in most PSC tumors. We identified two distinct molecular subtypes of PSC, driven primarily by immune infiltration and signaling. The Immune High (IM-H) subtype was associated with superior survival, highlighting the impact of immune infiltration on the biological and clinical features of localized PSCs. Conclusions: We provided detailed insight into the mutational landscape of PSC and identified two molecular subtypes associated with prognosis. IM-H tumors were associated with favorable recurrence-free survival and overall survival, highlighting the importance of tumor immune infiltration in the biological and clinical features of PSCs.

Treatment options for stage III-N2 pulmonary lymphoepithelioma-like carcinoma: A retrospective cohort study.

BACKGROUND AND PURPOSE: Pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare form of non-small cell lung carcinoma (NSCLC) that shares similarities with nasopharyngeal carcinoma. The optimal treatment for stage III-N2 PLELC remains controversial. METHODS AND MATERIALS: We conducted a retrospective analysis from stage III-N2 PLELC patients between 2009 and 2022 in our center. The patients were categorized into three groups: Group 1 (G1, definitive chemoradiotherapy), Group 2 (G2, radical surgery plus adjuvant chemoradiotherapy), and Group 3 (G3, radical surgery plus adjuvant chemotherapy). RESULTS: A total of 103 patients were included in the study, with 34, 25, and 44 patients in G1, G2, and G3, respectively. The median follow-up time was 47.4 months. The overall median PFS was 66.6 months, with 3-year PFS and 3-year OS rates of 66.0% and 92.4%, respectively, for all patients. Multivariate analysis revealed no significant difference in PFS between G1 and G2 (p = 0.354), while both groups exhibited significantly longer PFS than G3 (p < 0.001; p = 0.039). Similarly, no significant difference in OS was observed between G1 and G2 (p = 0.649), but both tended to demonstrate improved OS compared to G3 (p = 0.081; p = 0.092). Only one case of grade 3 radiation esophagitis was observed in G1, and no grade 3 or higher radiation pneumonitis were reported. CONCLUSIONS: Patients with stage III-N2 PLELC have a favorable prognosis, with radiotherapy playing a crucial role in treatment. Both definitive chemoradiotherapy and radical surgery followed by chemoradiotherapy demonstrate favorable efficacy and manageable toxicity.

Prognostic value of the immunohistochemical score based on four markers in head and neck squamous cell carcinoma.

Purpose: Head and neck squamous cell carcinoma (HNSCC) ranks sixth among all cancers globally regarding morbidity, and it has a poor prognosis, high mortality, and highly aggressive properties. In this study, we established a model for predicting prognosis based on immunohistochemical (IHC) scores. Methods: Data on 402 HNSCC cases were collected, the glmnet Cox proportional hazards model was used, risk factors were analyzed for predicting the prognosis of survival, and the IHC score was established. We used the IHC score to predict disease-free survival (DFS) using training and independent validation cohorts, including 264 cases in total. Additionally, the accuracy of the IHC score and the TNM system (8th edition) was compared. A DFS prediction nomogram was established by combining the prognostic factors. Results: The IHC scores included CK, Ki-67, p16, and p40 staining intensity. The concordance index and the Kaplan-Meier survival analysis showed that the IHC scores had high predictive power for HNSCC. Our results showed that the IHC score is an independent factor that can predict prognosis in a multivariate Cox regression analysis. When predicting DFS, the IHC score had a significantly higher value for the area under the ROC curve (AUC) than that of the TNM system. A nomogram was established and included the IHC score, age, tumor location, and the TNM stage. The calibration curves exhibited high consistency between the prognosis predicted by our nomogram and the actual prognosis. Conclusions: The IHC score was more accurate than the eighth edition of the TNM system in predicting HNSCC prognosis. Therefore, combining the two methods can facilitate individualized patient consultation and care.

Comparison of stereotactic body radiation therapy versus surgery for multiple primary lung cancers after prior radical resection: A multicenter retrospective study.

Background: Patients who previously underwent surgical resection of initial primary lung cancer are at a high risk of developing multiple primary lung cancers (MPLCs). The purpose of this study was to compare the efficacy and safety between stereotactic body radiation therapy (SBRT) and surgery for MPLCs patients after prior radical resection for the first lung cancers. Methods: In this multicenter retrospective study, eligible MPLC patients with tumor diameter of 5.0 cm or less at N0M0 who underwent SBRT or reoperation between January 2013 and August 2020 were enrolled. The primary endpoint was the 3-year locoregional recurrence and treatment-related toxicity. Kaplan-Meier method was used to calculate survival rates. The χ2 test was adapted to assess the difference of categorical variables between the two subgroup patients. Results: A total of 203 (73 in the SBRT group and 130 in the surgery group) patients from three academic cancer centers were evaluated with a median follow-up of 38.3 months. The cumulative 1-, 2-, and 3-year incidences of locoregional recurrence were 5.6 %, 7.0 % and 13.1 % in the SBRT group versus 3.2 %, 4.8 % and 7.4 % in the surgery group, respectively [hazard ratio (HR), 1.97; 95 % confidence interval (CI), 0.74-5.24; P = 0.14]. The cancer-specific survival rates were 95.9 %, 94.5 % and 88.1 % versus 96.9 %, 94.6 % and 93.8 % in the SBRT and surgery groups respectively (HR, 1.72; 95 % CI, 0.67-4.44; P = 0.23). In the SBRT group, two patients (2.7 %) suffered from grade 3 radiation pneumonitis, while in the surgery group, grade 3 complications occurred in four (3.1 %) patients, and four cases were expired due to pneumonia or pulmonary heart disease within 90 days after surgery. Conclusions: SBRT is an effective therapeutic option with limited toxicity compared to surgery for patients with MPLCs after prior radical surgical resection, and it could be considered as an alternative treatment for those patients.

Analysis of Immune Intratumor Heterogeneity Highlights Immunoregulatory and Coinhibitory Lymphocytes as Hallmarks of Recurrence in Stage I Non-Small Cell Lung Cancer.

Our understanding of the molecular mechanisms underlying postsurgical recurrence of non-small cell lung cancer (NSCLC) is rudimentary. Molecular and T cell repertoire intratumor heterogeneity (ITH) have been reported to be associated with postsurgical relapse; however, how ITH at the cellular level impacts survival is largely unknown. Here we report the analysis of 2880 multispectral images representing 14.2% to 27% of tumor areas from 33 patients with stage I NSCLC, including 17 cases (relapsed within 3 years after surgery) and 16 controls (without recurrence ≥5 years after surgery) using multiplex immunofluorescence. Spatial analysis was conducted to quantify the minimum distance between different cell types and immune cell infiltration around malignant cells. Immune ITH was defined as the variance of immune cells from 3 intratumor regions. We found that tumors from patients having relapsed display different immune biology compared with nonrecurrent tumors, with a higher percentage of tumor cells and macrophages expressing PD-L1 (P =.031 and P =.024, respectively), along with an increase in regulatory T cells (Treg) (P =.018), antigen-experienced T cells (P =.025), and effector-memory T cells (P =.041). Spatial analysis revealed that a higher level of infiltration of PD-L1+ macrophages (CD68+PD-L1+) or antigen-experienced cytotoxic T cells (CD3+CD8+PD-1+) in the tumor was associated with poor overall survival (P =.021 and P =.006, respectively). A higher degree of Treg ITH was associated with inferior recurrence-free survival regardless of tumor mutational burden (P =.022), neoantigen burden (P =.021), genomic ITH (P =.012) and T cell repertoire ITH (P =.001). Using multiregion multiplex immunofluorescence, we characterized ITH at the immune cell level along with whole exome and T cell repertoire sequencing from the same tumor regions. This approach highlights the role of immunoregulatory and coinhibitory signals as well as their spatial distribution and ITH that define the hallmarks of tumor relapse of stage I NSCLC.

Derived Neutrophil-Lymphocyte Ratio and C-Reactive Protein as Prognostic Factors for Early-Stage Non-Small Cell Lung Cancer Treated with Stereotactic Body Radiation Therapy.

Objectives: To explore the relationship between peripheral blood inflammation parameters and overall survival (OS) and progression-free survival (PFS) of early-stage non-small cell lung cancer patients who underwent stereotactic body radiotherapy (SBRT). Patients and methods: In this study, eligible patients treated with SBRT from 2013 to 2018, and both serum complete blood count and blood biochemical results were available prior to (within 60 days) radiotherapy were included. Results: A review of hospital registries identified 148 patients, and the 5-year OS and PFS of the entire cohort were 69.8% and 65.6%, respectively, with the median follow-up time was 52.8 months. Multivariable analysis showed that derived neutrophil-lymphocyte ratio (dNLR) ≥1.4 and C-reactive protein (CRP) ≥2.9 were statistically and independently associated with worse OS (HR = 4.62, 95% CI 1.89-11.27, p = 0.001; HR = 2.92, 95% CI 1.49-5.70, p = 0.002, respectively). The 5-year OS for patients with dNLR below and equal to or above the 1.4 were 85.3% and 62.9% (p = 0.002), respectively, and 76.7% for the low CRP group versus 58.5% for the high CRP group (p = 0.030). Higher serum level of post-treatment CRP also independent parameters for inferior PFS (HR = 4.83, 95% CI 1.28-18.25, p = 0.020). Conclusions: Our results demonstrate that dNLR and CRP are associated with the outcomes of early-stage NSCLC patients treated with SBRT, which may assist in selecting optimal nursing care and therapeutic scheme for every individual.

Analysis of genomic and immune intratumor heterogeneity in linitis plastica via multiregional exome and T-cell receptor sequencing.

The molecular landscape and the intratumor heterogeneity (ITH) architecture of gastric linitis plastica (LP) are poorly understood. We performed whole-exome sequencing (WES) and T-cell receptor (TCR) sequencing on 40 tumor regions from four LP patients. The landscape and ITH at the genomic and immunological levels in LP tumors were compared with multiple cancers that have previously been reported. The lymphocyte infiltration was further assessed by immunohistochemistry (IHC) in LP tumors. In total, we identified 6339 non-silent mutations from multi-samples, with a median tumor mutation burden (TMB) of 3.30 mutations per Mb, comparable to gastric adenocarcinoma from the Cancer Genome Atlas (TCGA) cohort (P = 0.53). An extremely high level of genomic ITH was observed, with only 12.42%, 5.37%, 5.35%, and 30.67% of mutations detectable across 10 regions within the same tumors of each patient, respectively. TCR sequencing revealed that TCR clonality was substantially lower in LP than in multi-cancers. IHC using antibodies against CD4, CD8, and PD-L1 demonstrated scant T-cell infiltration in the four LP tumors. Furthermore, profound TCR ITH was observed in all LP tumors, with no T-cell clones shared across tumor regions in any of the patients, while over 94% of T-cell clones were restricted to individual tumor regions. The Morisita overlap index (MOI) ranged from 0.21 to 0.66 among multi-regions within the same tumors, significantly lower than that of lung cancer (P = 0.002). Our results show that LP harbored extremely high genomic and TCR ITH and suppressed T-cell infiltration, suggesting a potential contribution to the frequent recurrence and poor therapeutic response of this adenocarcinoma.

Immunogenomic profiling of lung adenocarcinoma reveals poorly differentiated tumors are associated with an immunogenic tumor microenvironment.

OBJECTIVES: Pathologists have routinely observed distinct histologic patterns of growth in early-stage lung adenocarcinoma (LUAD), which have been suggested to be associated with prognosis. Herein, we investigated the relationship between LUAD patterns of growth, as defined by the updated international association for the study of lung cancer (IASLC) grading criteria, and differences in the tumor immune microenvironment to identify predictors of response to immunotherapy. METHODS: 174 resected stage I-III LUAD tumors were classified by histologic pattern of growth (i.e. solid, micropapillary, acinar, papillary, and lepidic) and then grouped as well differentiated, moderately differentiated, and poorly differentiated. Comprehensive multiplatform analysis including whole exome sequencing, gene expression profiling, immunohistochemistry, CIBERSORT, and T-cell receptor sequencing was performed and groups were compared for differences in genomic drivers, immune cell infiltrate, clonality, and survival. Finally, multivariate analysis was performed adjusting for pathologic stage and smoking status. RESULTS: Poorly differentiated tumors demonstrated a strong association with smoking relative to moderately differentiated or well differentiated tumors. However, unlike in prior reports, poorly differentiated tumors were not associated with a worse survival after curative-intent resection. Genomic analysis revealed that poorly differentiated tumors are associated with high tumor mutation burden but showed no association with oncogenic drivers. Immune analyses revealed that poorly differentiated tumors are associated with increased T-cell clonality, expression of PD-L1, and infiltration by cytotoxic CD8 T-cells, activated CD4 T-cells, and pro-inflammatory (M1) macrophages. Finally, multivariate analysis controlling for stage and smoking status confirmed independence of immune differences between IASLC grade groups. CONCLUSIONS: Poorly differentiated tumors, as defined by the updated IASLC grading criteria, are associated with a distinct immunogenic tumor microenvironment that predicts for therapeutic response to immune agents, including checkpoint inhibitors, and should be included in the clinical trial design of immunotherapy studies in early-stage lung adenocarcinoma.

Immunogenomic intertumor heterogeneity across primary and metastatic sites in a patient with lung adenocarcinoma.

BACKGROUND: Lung cancer is the leading cause of cancer death, partially owing to its extensive heterogeneity. The analysis of intertumor heterogeneity has been limited by an inability to concurrently obtain tissue from synchronous metastases unaltered by multiple prior lines of therapy. METHODS: In order to study the relationship between genomic, epigenomic and T cell repertoire heterogeneity in a rare autopsy case from a 32-year-old female never-smoker with left lung primary late-stage lung adenocarcinoma (LUAD), we did whole-exome sequencing (WES), DNA methylation and T cell receptor (TCR) sequencing to characterize the immunogenomic landscape of one primary and 19 synchronous metastatic tumors. RESULTS: We observed heterogeneous mutation, methylation, and T cell patterns across distinct metastases. Only TP53 mutation was detected in all tumors suggesting an early event while other cancer gene mutations were later events which may have followed subclonal diversification. A set of prevalent T cell clonotypes were completely excluded from left-side thoracic tumors indicating distinct T cell repertoire profiles between left-side and non left-side thoracic tumors. Though a limited number of predicted neoantigens were shared, these were associated with homology of the T cell repertoire across metastases. Lastly, ratio of methylated neoantigen coding mutations was negatively associated with T-cell density, richness and clonality, suggesting neoantigen methylation may partially drive immunosuppression. CONCLUSIONS: Our study demonstrates heterogeneous genomic and T cell profiles across synchronous metastases and how restriction of unique T cell clonotypes within an individual may differentially shape the genomic and epigenomic landscapes of synchronous lung metastases.

Cold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer.

Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, using multi-region whole exome/T cell receptor (TCR) sequencing as well as immunohistochemistry, we reveal a rather homogeneous mutational landscape but extremely cold and heterogeneous TCR repertoire in limited-stage SCLC tumors (LS-SCLCs). Compared to localized non-small cell lung cancers, LS-SCLCs have similar predicted neoantigen burden and genomic ITH, but significantly colder and more heterogeneous TCR repertoire associated with higher chromosomal copy number aberration (CNA) burden. Furthermore, copy number loss of IFN-γ pathway genes is frequently observed and positively correlates with CNA burden. Higher mutational burden, higher T cell infiltration and positive PD-L1 expression are associated with longer overall survival (OS), while higher CNA burden is associated with shorter OS in patients with LS-SCLC.

Immune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features.

The mechanism by which anti-cancer immunity shapes early carcinogenesis of lung adenocarcinoma (ADC) is unknown. In this study, we characterize the immune contexture of invasive lung ADC and its precursors by transcriptomic immune profiling, T cell receptor (TCR) sequencing and multiplex immunofluorescence (mIF). Our results demonstrate that anti-tumor immunity evolved as a continuum from lung preneoplasia, to preinvasive ADC, minimally-invasive ADC and frankly invasive lung ADC with a gradually less effective and more intensively regulated immune response including down-regulation of immune-activation pathways, up-regulation of immunosuppressive pathways, lower infiltration of cytotoxic T cells (CTLs) and anti-tumor helper T cells (Th), higher infiltration of regulatory T cells (Tregs), decreased T cell clonality, and lower frequencies of top T cell clones in later-stages. Driver mutations, chromosomal copy number aberrations (CNAs) and aberrant DNA methylation may collectively impinge host immune responses and facilitate immune evasion, promoting the outgrowth of fit subclones in preneoplasia into dominant clones in invasive ADC.

Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas.

The evolution of DNA methylome and methylation intra-tumor heterogeneity (ITH) during early carcinogenesis of lung adenocarcinoma has not been systematically studied. We perform reduced representation bisulfite sequencing of invasive lung adenocarcinoma and its precursors, atypical adenomatous hyperplasia, adenocarcinoma in situ and minimally invasive adenocarcinoma. We observe gradual increase of methylation aberrations and significantly higher level of methylation ITH in later-stage lesions. The phylogenetic patterns inferred from methylation aberrations resemble those based on somatic mutations suggesting parallel methylation and genetic evolution. De-convolution reveal higher ratio of T regulatory cells (Tregs) versus CD8 + T cells in later-stage diseases, implying progressive immunosuppression with neoplastic progression. Furthermore, increased global hypomethylation is associated with higher mutation burden, copy number variation burden and AI burden as well as higher Treg/CD8 ratio, highlighting the potential impact of methylation on chromosomal instability, mutagenesis and tumor immune microenvironment during early carcinogenesis of lung adenocarcinomas.

Characterization of the Immune Landscape of EGFR-Mutant NSCLC Identifies CD73/Adenosine Pathway as a Potential Therapeutic Target.

INTRODUCTION: Lung adenocarcinomas harboring EGFR mutations do not respond to immune checkpoint blockade therapy and their EGFR wildtype counterpart. The mechanisms underlying this lack of clinical response have been investigated but remain incompletely understood. METHODS: We analyzed three cohorts of resected lung adenocarcinomas (Profiling of Resistance Patterns of Oncogenic Signaling Pathways in Evaluation of Cancer of Thorax, Immune Genomic Profiling of NSCLC, and The Cancer Genome Atlas) and compared tumor immune microenvironment of EGFR-mutant tumors to EGFR wildtype tumors, to identify actionable regulators to target and potentially enhance the treatment response. RESULTS: EGFR-mutant NSCLC exhibited low programmed death-ligand 1, low tumor mutational burden, decreased number of cytotoxic T cells, and low T cell receptor clonality, consistent with an immune-inert phenotype, though T cell expansion ex vivo was preserved. In an analysis of 75 immune checkpoint genes, the top up-regulated genes in the EGFR-mutant tumors (NT5E and ADORA1) belonged to the CD73/adenosine pathway. Single-cell analysis revealed that the tumor cell population expressed CD73, both in the treatment-naive and resistant tumors. Using coculture systems with EGFR-mutant NSCLC cells, T regulatory cell proportion was decreased with CD73 knockdown. In an immune-competent mouse model of EGFR-mutant lung cancer, the CD73/adenosine pathway was markedly up-regulated and CD73 blockade significantly inhibited tumor growth. CONCLUSIONS: Our work revealed that EGFR-mutant NSCLC has an immune-inert phenotype. We identified the CD73/adenosine pathway as a potential therapeutic target for EGFR-mutant NSCLC.

Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity.

BACKGROUND: Metastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths. Our understanding of the molecular mechanisms driving metastasis is rudimentary. RESULTS: We perform whole exome sequencing (WES), RNA sequencing, methylation microarray, and immunohistochemistry (IHC) on 8 pairs of non-small cell lung cancer (NSCLC) primary tumors and matched distant metastases. Furthermore, we analyze published WES data from 35 primary NSCLC and metastasis pairs, and transcriptomic data from 4 autopsy cases with metastatic NSCLC and one metastatic lung cancer mouse model. The majority of somatic mutations are shared between primary tumors and paired distant metastases although mutational signatures suggest different mutagenesis processes in play before and after metastatic spread. Subclonal analysis reveals evidence of monoclonal seeding in 41 of 42 patients. Pathway analysis of transcriptomic data reveals that downregulated pathways in metastases are mainly immune-related. Further deconvolution analysis reveals significantly lower infiltration of various immune cell types in metastases with the exception of CD4+ T cells and M2 macrophages. These results are in line with lower densities of immune cells and higher CD4/CD8 ratios in metastases shown by IHC. Analysis of transcriptomic data from autopsy cases and animal models confirms that immunosuppression is also present in extracranial metastases. Significantly higher somatic copy number aberration and allelic imbalance burdens are identified in metastases. CONCLUSIONS: Metastasis is a molecularly late event, and immunosuppression driven by different molecular events, including somatic copy number aberration, may be a common characteristic of tumors with metastatic plasticity.

Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas.

Autologous chimeric antigen receptor (CAR) T cell therapies targeting CD19 have high efficacy in large B cell lymphomas (LBCLs), but long-term remissions are observed in less than half of patients, and treatment-associated adverse events, such as immune effector cell-associated neurotoxicity syndrome (ICANS), are a clinical challenge. We performed single-cell RNA sequencing with capture-based cell identification on autologous axicabtagene ciloleucel (axi-cel) anti-CD19 CAR T cell infusion products to identify transcriptomic features associated with efficacy and toxicity in 24 patients with LBCL. Patients who achieved a complete response by positron emission tomography/computed tomography at their 3-month follow-up had three-fold higher frequencies of CD8 T cells expressing memory signatures than patients with partial response or progressive disease. Molecular response measured by cell-free DNA sequencing at day 7 after infusion was significantly associated with clinical response (P = 0.008), and a signature of CD8 T cell exhaustion was associated (q = 2.8 × 10-149) with a poor molecular response. Furthermore, a rare cell population with monocyte-like transcriptional features was associated (P = 0.0002) with high-grade ICANS. Our results suggest that heterogeneity in the cellular and molecular features of CAR T cell infusion products contributes to variation in efficacy and toxicity after axi-cel therapy in LBCL, and that day 7 molecular response might serve as an early predictor of CAR T cell efficacy.

The E2 ubiquitin-conjugating enzyme UbcH5c: an emerging target in cancer and immune disorders.

Ubiquitination is a crucial post-translational modification (PTM) of proteins and regulates their stabilities and activities, thereby modulating multiple signaling pathways. UbcH5c, a member of the UbcH5 ubiquitin-conjugating enzyme (E2) protein family, engages in the ubiquitination of dozens of proteins and regulates nuclear factor kappa-B (NF-κB), p53 tumor suppressor, and several other essential signaling pathways. UbcH5c has been reported to be abnormally expressed in human cancer and immune disorders and is involved in the initiation and progression of these diseases. In this review, we mainly focus on UbcH5c structure, activity, signaling pathways, and its relevance to cancer and immune disorders. We end by integrating all known factors relating to UbcH5c inhibition as a potential cancer therapy method, and discuss associated challenges.

Evolution of Genomic and T-cell Repertoire Heterogeneity of Malignant Pleural Mesothelioma Under Dasatinib Treatment.

PURPOSE: Malignant pleural mesothelioma (MPM) is considered an orphan disease with few treatment options. Despite multimodality therapy, the majority of MPMs recur and eventually become refractory to any systemic treatment. One potential mechanism underlying therapeutic resistance may be intratumor heterogeneity (ITH), making MPM challenging to eradicate. However, the ITH architecture of MPM and its clinical impact have not been well studied. EXPERIMENTAL DESIGN: We delineated the immunogenomic ITH by multiregion whole-exome sequencing and T-cell receptor (TCR) sequencing of 69 longitudinal MPM specimens from nine patients with resectable MPM, who were treated with dasatinib. RESULTS: The median total mutation burden before dasatinib treatment was 0.65/Mb, similar with that of post-dasatinib treatment (0.62/Mb). The median proportion of mutations shared by any given pair of two tumor regions within the same tumors was 80% prior to and 83% post-dasatinib treatment indicating a relatively homogenous genomic landscape. T-cell clonality, a parameter indicating T-cell expansion and reactivity, was significantly increased in tumors after dasatinib treatment. Furthermore, on average, 82% of T-cell clones were restricted to individual tumor regions, with merely 6% of T-cell clones shared by all regions from the same tumors indicating profound TCR heterogeneity. Interestingly, patients with higher T-cell clonality and higher portion of T cells present across all tumor regions in post-dasatinib-treated tumors had significantly longer survival. CONCLUSIONS: Despite the homogeneous genomic landscape, the TCR repertoire is extremely heterogeneous in MPM. Dasatinib may potentially induce T-cell response leading to improved survival.