Leveraging immune resistance archetypes in solid cancer to inform next-generation anticancer therapies.

Anticancer immunotherapies, such as immune checkpoint inhibitors, bispecific antibodies, and chimeric antigen receptor T cells, have improved outcomes for patients with a variety of malignancies. However, most patients either do not initially respond or do not exhibit durable responses due to primary or adaptive/acquired immune resistance mechanisms of the tumor microenvironment. These suppressive programs are myriad, different between patients with ostensibly the same cancer type, and can harness multiple cell types to reinforce their stability.

Production of an interleukin-10 blocking antibody by genetically engineered macrophages increases cancer cell death in human gastrointestinal tumor slice cultures.

Although it can promote effector T-cell function, the summative effect of interleukin-10 (IL-10) in the tumor microenvironment (TME) appears to be suppressive; therefore, blocking this critical regulatory cytokine has therapeutic potential to enhance antitumor immune function. As macrophages efficiently localize to the TME, we hypothesized that they could be used as a delivery vehicle for drugs designed to block this pathway. To test our hypothesis, we created and evaluated genetically engineered macrophages (GEMs) that produce an IL-10-blocking antibody (αIL-10).

An In Vivo Model of Human Macrophages in Metastatic Melanoma.

Despite recent therapeutic progress, advanced melanoma remains lethal for many patients. The composition of the immune tumor microenvironment (TME) has decisive impacts on therapy response and disease outcome, and high-dimensional analyses of patient samples reveal the heterogeneity of the immune TME. Macrophages infiltrate TMEs and generally associate with tumor progression, but the underlying mechanisms are incompletely understood.

Blockade of interleukin 10 potentiates antitumour immune function in human colorectal cancer liver metastases.

Objective: Programmed cell death protein 1 (PD-1) checkpoint inhibition and adoptive cellular therapy have had limited success in patients with microsatellite stable colorectal cancer liver metastases (CRLM). We sought to evaluate the effect of interleukin 10 (IL-10) blockade on endogenous T cell and chimeric antigen receptor T (CAR-T) cell antitumour function in CRLM slice cultures.

Design: We created organotypic slice cultures from human CRLM (n=38 patients' tumours) and tested the antitumour effects of a neutralising antibody against IL-10 (αIL-10) both alone as treatment and in combination with exogenously administered carcinoembryonic antigen (CEA)-specific CAR-T cells.

Neoantigen-specific CD4 T cells in human melanoma have diverse differentiation states and correlate with CD8 T cell, macrophage, and B cell function.

CD4 T cells that recognize tumor antigens are required for immune checkpoint inhibitor efficacy in murine models, but their contributions in human cancer are unclear. We used single-cell RNA sequencing and T cell receptor sequences to identify signatures and functional correlates of tumor-specific CD4 T cells infiltrating human melanoma. Conventional CD4 T cells that recognize tumor neoantigens express CXCL13 and are subdivided into clusters expressing memory and T follicular helper markers, and those expressing cytolytic markers, inhibitory receptors, and IFN-γ.

Neoadjuvant Therapy Induces a Potent Immune Response to Sarcoma, Dominated by Myeloid and B Cells.

Purpose: To characterize changes in the soft-tissue sarcoma (STS) tumor immune microenvironment induced by standard neoadjuvant therapy with the goal of informing neoadjuvant immunotherapy trial design.

Experimental Design: Paired pre- and postneoadjuvant therapy specimens were retrospectively identified for 32 patients with STSs and analyzed by three modalities: multiplexed IHC, NanoString, and RNA sequencing with ImmunoPrism analysis.

Results: All 32 patients, representing a variety of STS histologic subtypes, received neoadjuvant radiotherapy and 21 (66%) received chemotherapy prior to radiotherapy.

CD4+ T cell and M2 macrophage infiltration predict dedifferentiated liposarcoma patient outcomes.

Background: Dedifferentiated liposarcoma (DDLPS) is one of the most common soft tissue sarcoma subtypes and is devastating in the advanced/metastatic stage. Despite the observation of clinical responses to inhibitors, little is known about the immune microenvironment in relation to patient prognosis.

Methods: We performed a retrospective study of 61 patients with DDLPS.

Key chemokines direct migration of immune cells in solid tumors.

Immune cell infiltration into solid tumors, their movement within the tumor microenvironment (TME), and interaction with other immune cells are controlled by their directed migration towards gradients of chemokines. Dysregulated chemokine signaling in TME favors the growth of tumors, exclusion of effector immune cells, and abundance of immunosuppressive cells. Key chemokines directing the migration of immune cells into tumor tissue have been identified.

Long-term Outcomes for Extraskeletal Myxoid Chondrosarcoma: A SEER Database Analysis.

Background: Extraskeletal myxoid chondrosarcoma (EMCS) is a rare tumor that typically has an indolent course but high rate of recurrence. We queried the Surveillance, Epidemiology, and End Results (SEER) database to assess factors associated with metastasis, treatment, and survival.

Methods: We queried the SEER 1973-2016 database for patients with myxoid chondrosarcoma (ICD-O-3: 9231/3).

Correction to: Rates of TP53 Mutation are Significantly Elevated in African American Patients with Gastric Cancer.

In the original article Kaitlin C. McLoughlin's name is spelled incorrectly. It is correct as reflected here.

Age-Specific Incidence of Melanoma in the United States.

Importance: Melanoma is epidemiologically linked to UV exposure, particularly childhood sunburn. Public health campaigns are increasing sun-protective behavior in the United States, but the effect on melanoma incidence is unknown.

Objective: To examine the incidence of melanoma in the United States and whether any age-specific differences are present.

Intratumoral Immune Response to Gastric Cancer Varies by Molecular and Histologic Subtype.

Immune checkpoint inhibition is effective in a subset of patients with advanced gastric cancer. Genomic profiling has revealed the heterogeneity of gastric adenocarcinomas, but the immune microenvironment and predictors of immunotherapy response remain poorly understood. We aimed to better characterize the underlying immune response to gastric cancer.

Mobilization of CD8 T Cells via CXCR4 Blockade Facilitates PD-1 Checkpoint Therapy in Human Pancreatic Cancer.

Purpose: Pancreatic ductal adenocarcinoma (PDA) is rarely cured, and single-agent immune checkpoint inhibition has not demonstrated clinical benefit despite the presence of large numbers of CD8 T cells. We hypothesized that tumor-infiltrating CD8 T cells harbor latent antitumor activity that can be reactivated using combination immunotherapy.

Experimental Design: Preserved human PDA specimens were analyzed using multiplex IHC (mIHC) and T-cell receptor (TCR) sequencing.

Rates of TP53 Mutation are Significantly Elevated in African American Patients with Gastric Cancer.

Background: Gastric adenocarcinoma is a heterogenous disease that results from complex interactions between environmental and genetic factors, which may contribute to the disparate outcomes observed between different patient populations. This study aimed to determine whether genomic differences exist in a diverse population of patients by evaluating tumor mutational profiles stratified by race.

Methods: All patients with gastric adenocarcinoma between 2012 and 2016 who underwent targeted next-generation sequencing of cancer genes by the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets platform were identified.

ETV4 collaborates with Wnt/β-catenin signaling to alter cell cycle activity and promote tumor aggressiveness in gastrointestinal stromal tumor.

Gastrointestinal stromal tumor (GIST) is the most common sarcoma, often resulting from a or platelet-derived growth factor receptor alpha () mutation. The lineage transcription factor ETV1 is expressed similarly in GISTs regardless of malignant potential. Although the related transcription factor ETV4 has been associated with metastasis and tumor progression in other cancers, its role in GIST is unknown.

Wnt/β-catenin Signaling Contributes to Tumor Malignancy and Is Targetable in Gastrointestinal Stromal Tumor.

Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma and usually harbors either a or mutation. However, the molecular basis for tumor malignancy is not well defined. Although the Wnt/β-catenin signaling pathway is important in a variety of cancers, its role in GIST is uncertain.

Genome and transcriptome profiling of fibrolamellar hepatocellular carcinoma demonstrates p53 and IGF2BP1 dysregulation.

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of HCC that most frequently affects young adults. Because of its rarity and an absence of preclinical models, our understanding of FL-HCC is limited. Our objective was to analyze chromosomal alterations and dysregulated gene expression in tumor specimens collected at a single center during two decades of experience with FL-HCC.

PD-1/PD-L1 Blockade Enhances T-cell Activity and Antitumor Efficacy of Imatinib in Gastrointestinal Stromal Tumors.

Purpose: Tyrosine kinase inhibitors are effective in gastrointestinal stromal tumors (GISTs) but often are of transient benefit as resistance commonly develops. Immunotherapy, particularly blockade of the inhibitory receptor programmed death 1 (PD-1) or the ligand programmed death ligand 1 (PD-L1), has shown effectiveness in a variety of cancers. The functional effects of PD-1/PD-L1 blockade are unknown in GISTs.

Principles of Kinase Inhibitor Therapy for Solid Tumors.

Objective: We aimed to identify key principles of targeted therapy of protein kinases and their application to the management of solid tumors.

Background: Concurrent advances in tumor genomic analysis and molecular inhibitor development have dramatically impacted the diagnosis and treatment of solid tumors, and common themes regarding the use of kinase inhibitors are developing.

Methods: The list of kinase inhibitors that have been approved by the US Food and Drug Administration was reviewed and articles related to the agents were searched in the PubMed database up until December 2015.

Diagnosis and Management of Pancreatic Cystic Neoplasms.

Incidentally discovered pancreatic cystic lesions are increasingly common, affecting up to 10% to 15% of patients undergoing cross-sectional imaging. Although some pancreatic cystic neoplasms harbor invasive malignancy or the potential to progress over time, a majority are benign and can be observed safely. Accurate diagnosis is key to appropriate management.

Pharmacological Inhibition of KIT Activates MET Signaling in Gastrointestinal Stromal Tumors.

Gastrointestinal stromal tumors (GIST) are the most common adult sarcomas and the oncogenic driver is usually a KIT or PDGFRA mutation. Although GISTs are often initially sensitive to imatinib or other tyrosine kinase inhibitors, resistance generally develops, necessitating backup strategies for therapy. In this study, we determined that a subset of human GIST specimens that acquired imatinib resistance acquired expression of activated forms of the MET oncogene.

RETRACTED: CD44 expression denotes a subpopulation of gastric cancer cells in which Hedgehog signaling promotes chemotherapy resistance.

Purpose: Gastric cancers may harbor a subset of cells with cancer stem cell (CSC) properties, including chemotherapy resistance, and CD44 is a gastric CSC marker. The Hedgehog (HH) pathway is a key developmental pathway that can be subverted by CSCs during tumorigenesis. Here, we examine the role of HH signaling in CD44(+) gastric cancer cells.