CD103+ regulatory T cells underlie resistance to radio-immunotherapy and impair CD8+ T cell activation in glioblastoma.

Glioblastomas are aggressive primary brain tumors with an inherent resistance to T cell-centric immunotherapy due to their low mutational burden and immunosuppressive tumor microenvironment. Here we report that fractionated radiotherapy of preclinical glioblastoma models induce a tenfold increase in T cell content. Orthogonally, spatial imaging mass cytometry shows T cell enrichment in human recurrent tumors compared with matched primary glioblastoma. In glioblastoma-bearing mice, α-PD-1 treatment applied at the peak of T cell infiltration post-radiotherapy results in a modest survival benefit compared with concurrent α-PD-1 administration. Following α-PD-1 therapy, CD103+ regulatory T cells (Tregs) with upregulated lipid metabolism accumulate in the tumor microenvironment, and restrain immune checkpoint blockade response by repressing CD8+ T cell activation. Treg targeting elicits tertiary lymphoid structure formation, enhances CD4+ and CD8+ T cell frequency and function and unleashes radio-immunotherapeutic efficacy. These results support the rational design of therapeutic regimens limiting the induction of immunosuppressive feedback pathways in the context of T cell immunotherapy in glioblastoma.

Treatment Patterns of Real-World Patients with TRK Fusion Cancer Treated by US Community Oncologists.

BACKGROUND: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are present across various tumor types with an estimated overall prevalence of less than 1%. Tropomyosin receptor kinase inhibitors (TRKis) block the constitutively activated tyrosine receptor kinase (TRK) fusion protein produced in cancers with NTRK gene fusions (NTRK+) from downstream signaling. Many treatment guidelines now include TRKis as first-line (1L) or subsequent treatment options for TRK fusion cancer. OBJECTIVE: This study aimed to assess treatment patterns subsequent to a finding of NTRK+ status among patients with TRK fusion cancer. PATIENTS AND METHODS: This was a one-time, retrospective, multi-site patient chart abstraction by oncology practices in the USA from June to September 2020. US medical oncologists from the Oncology Provider Extended Network (OPEN) who had treated patients with NTRK+ advanced/metastatic solid tumors abstracted information into electronic case report forms (eCRFs) for adult patients with advanced/metastatic solid tumors and a NTRK+ tumor test result with a known fusion partner. Data abstracted into eCRFs by oncologists included demographic, clinical, and treatment characteristics of patients with advanced/metastatic TRK fusion solid tumors. Responses were summarized using descriptive statistics. Median treatment durations across the lines of therapy were estimated by Kaplan-Meier time to discontinuation. RESULTS: A total of 19 medical oncologists abstracted data from 110 patient charts. Median patient age at advanced/metastatic diagnosis was 62 years. The majority of patients were male (58.2%) and White (79.1%). Solid tumor types reported in at least 10% of the study cohort were lung (24.5%), cholangiocarcinoma (13.6%), pancreatic (10.9%), and colorectal (10.0%). Results for patients with hepatobiliary cancers (i.e., cholangiocarcinoma, pancreatic cancer, hepatocellular carcinoma) and colorectal cancer, and appendiceal cancer are also included. Median duration of 1L TRKi therapy was 16.8 months across all solid tumor types, whereas median duration of 1L was 5.6 months among patients receiving non-TRKi therapies (p = 0.017). Among the solid tumor types represented by at least 10% of the study population, median duration of 1L TRKi therapy was only reached in patients with pancreatic cancer (3.3 months). Median duration of TRKi in the second-line (2L) setting was 7.9 months overall, relative to 5.3 months among patients receiving non-TRKi therapies (p = 0.003). Across lung, cholangiocarcinoma, pancreatic, and colorectal cancers, the median durations of 2L TRKi therapy were 14.1, 6.0, 6.1, and 4.1 months, respectively. CONCLUSION AND RELEVANCE: Among patients with advanced/metastatic TRK fusion solid tumors, medical oncologists reported that approximately two-thirds initiated a TRKi during the study period. Treatment with a TRKi was longer in duration compared to non-TRKi treatment in 1L and 2L therapy. Additional research is needed to gain insight into the association between early TRKi therapy initiation and clinical outcomes in the real-world setting.

Timing of NTRK Gene Fusion Testing and Treatment Modifications Following TRK Fusion Status Among US Oncologists Treating TRK Fusion Cancer.

BACKGROUND: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers with an estimated prevalence of less than 1% across all solid tumors. Tropomyosin receptor kinase inhibitors (TRKis) block the constitutively activated tyrosine receptor kinase (TRK) fusion protein produced in NTRK gene fusion positive (NTRK+) tumors from downstream signaling. Tropomyosin receptor kinase inhibitors are now first-line (1L) or subsequent treatment options for TRK fusion cancers. OBJECTIVE: This study assessed timing of NTRK gene fusion testing and treatment modifications among patients with TRK fusion cancers. PATIENTS AND METHODS: This was a one-time physician questionnaire with a retrospective, multisite patient chart abstraction of oncology practices in the USA. From June to September 2020, medical oncologists from the Oncology Provider Extended Network (OPEN) who treated patients with NTRK+ advanced/metastatic solid tumors abstracted information into electronic case report forms (eCRFs) for adult patients with advanced/metastatic solid tumors and a NTRK+ tumor test result with a known fusion partner. Use of NTRK testing in routine clinical practice among patients with advanced/metastatic solid tumors was assessed. Data included demographic, clinical, and NTRK gene fusion testing characteristics. Responses were summarized using descriptive statistics. RESULTS: Twenty-eight community-based medical oncologists who had managed or treated 148 patients with advanced/metastatic TRK fusion cancer between 01/01/2016 and 12/31/2019 completed the survey. Lung (27%), thyroid (18%), salivary gland (14%), and colorectal (12%) were the most commonly reported tumor types. A majority (68%) tested NTRK status prior to 1L initiation; testing after disease progression on 1L (36%), 2L (25%), and 3L (21%) was also noted. Most oncologists (96%) reported no difficulty interpreting NTRK reports. Nearly all (96%) indicated using next-generation sequencing (NGS) for determining NTRK status. The majority (57%) indicated that age, tumor type, and performance status did not impact NTRK testing decisions. Less than half (46%) include TRKi therapy following NTRK+ determination. NTRK testing guidelines were commonly reviewed by physicians (89%). CONCLUSION AND RELEVANCE: Among patients with advanced/metastatic TRK fusion cancer, medical oncologists reported testing for NTRK fusions at diagnosis or prior to 1L. Future research should elucidate why fewer than half of oncologists surveyed (46%) would not use TRKis after NTRK+ status confirmation, assess clinical practices among NTRK+ patients, and characterize treatment patterns and clinical outcomes in real-world settings.

Adenocarcinoma of the Uterine Cervix Shows Impaired Recruitment of cDC1 and CD8+ T Cells and Elevated ß-Catenin Activation Compared with Squamous Cell Carcinoma.

PURPOSE: Adenocarcinoma of the uterine cervix is the second most common type of cervical cancer after squamous cell carcinoma (SCC). Although both subtypes are treated similarly, patients with adenocarcinoma have a worse prognosis. In this study, immunologic features of the tumor microenvironment in these two subsets were pursued with potential therapeutic implications. EXPERIMENTAL DESIGN: The immune microenvironment of primary tumors and nonmetastatic tumor-draining lymph nodes (TDLN) was compared between patients with cervical adenocarcinoma (n = 16) and SCC (n = 20) by polychromatic flow cytometry and by transcriptional profiling of the primary tumors (n = 299) using publicly available data from The Cancer Genome Atlas (TCGA). RESULTS: Flow cytometric analyses revealed intact T-cell differentiation in TDLNs, but hampered effector T-cell trafficking to the primary tumors in adenocarcinoma, as compared with SCC. TCGA analysis demonstrated higher expression of chemokines involved in effector T-cell homing (CXCL9/10/11) in SCC primary tumors as compared with adenocarcinoma primary tumors, which was highly correlated to a transcriptional signature for type I conventional dendritic cells (cDC1). This was consistent with elevated frequencies of CD141/BDCA3+cDC1 in primary tumor SCC samples relative to adenocarcinoma and correspondingly elevated levels of CXCL9 and CXCL10 in 24-hour ex vivo cultures. Hampered cDC1 recruitment in adenocarcinoma was in turn related to lower transcript levels of cDC1-recruiting chemokines and an elevated ß-catenin activation score and was associated with poor overall survival. CONCLUSIONS: Our data have identified an opportunity for the investigation of potentially novel therapeutic interventions in adenocarcinoma of the cervix, that is, ß-catenin inhibition and cDC1 mobilization.