No abstract

Tumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines. Based on the premise that cancer is fundamentally a disorder of the genes arising within a cell biologic process, whose deviations from normality determine the rules of engagement with the host’s response, the Society for Immunotherapy of Cancer (SITC) convened a task force of experts from various disciplines including, immunology, oncology, biophysics, structural biology, molecular and cellular biology, genetics, and bioinformatics to address the complexity of CIR from a holistic view. The task force was launched by a workshop held in San Francisco on May 14–15, 2018 aimed at two preeminent goals: 1) to identify the fundamental questions related to CIR and 2) to create an interactive community of experts that could guide scientific and research priorities by forming a logical progression supported by multiple perspectives to uncover mechanisms of CIR. This workshop was a first step toward a second meeting where the focus would be to address the actionability of some of the questions identified by working groups. In this event, five working groups aimed at defining a path to test hypotheses according to their relevance to human cancer and identifying experimental models closest to human biology, which include: 1) Germline-Genetic, 2) Somatic-Genetic and 3) Genomic-Transcriptional contributions to CIR, 4) Determinant(s) of Immunogenic Cell Death that modulate CIR, and 5) Experimental Models that best represent CIR and its conversion to an immune responsive state. This manuscript summarizes the contributions from each group and should be considered as a first milestone in the path toward a more contemporary understanding of CIR. We appreciate that this effort is far from comprehensive and that other relevant aspects related to CIR such as the microbiome, the individual’s recombined T cell and B cell receptors, and the metabolic status of cancer and immune cells were not fully included. These and other important factors will be included in future activities of the taskforce. The taskforce will focus on prioritization and specific actionable approach to answer the identified questions and implementing the collaborations in the follow-up workshop, which will be held in Houston on September 4–5, 2019.

CD44 is a receptor for hyaluronic acid and is found on the surface of hematopoetic cells and in mesenchymal tissue. It is also expressed on endothelial cells (EC). Cyclooxygenase (COX) is the rate-limiting enzyme in the production of prostaglandins in EC. Here we show that engagement of CD44 with signaling monoclonal antibodies (mAbs) or its natural ligand hyaluronic acid induces COX-2 and prostacyclin (PGI 2 ) formation in human EC. This induction was blocked by mAbs that have been shown to inhibit CD44-mediated intracellular signaling. COX-1 induction was not observed after CD44 ligation. CD44-stimulated COX-2 activation/PGI 2 production was accompanied by the production of the potent endothelial mitogen, vascular endothelial growth factor (VEGF) and was inhibited by a neutralizing VEGF antibody. Moreover, this COX-2 induction was also associated with an increase in EC proliferation that was inhibited by the blocking anti-CD44 mAbs and a COX-2-specific inhibitor. This is the first study to show that engagement of CD44 with mAbs or its natural ligand induces COX-2, generates VEGF, and thus leads to an increase in EC proliferation. Results from this study may have important and widespread implications for the development of novel therapeutic agents for modulating blood vessel growth during ischemic heart disease, during inflammation, or around solid tumors.Key words: vascular endothelial growth factor • prostacyclin • COX he cell adhesion molecule CD44 is involved in a variety of important biological events such as embryogenesis, hematopoiesis, lymphocyte homing and activation, inflammatory reactions, and tumor dissemination (1-4). CD44 represents a large protein family, which includes the standard form or CD44 with a molecular mass of 85-90 kDa, and a multiplicity of isoforms generated by alternative splicing of transcripts and subsequent variable glycosylation (reviewed in ref 5). These high molecular mass variants are rarely expressed on normal cells. CD44 is the principal cell surface receptor for extracellular matrix glycosaminoglycan hyaluronan (HA). CD44-HA-mediated cell adhesion is important in several pathophysiological processes such as inflammation and metastatic spread of cancer cells. In this context, it has been recognized that CD44 can function as a signaling receptor in a variety of cell types (6). Cell stimulation by monoclonal anti-CD44 antibody or natural CD44 ligands activate signaling pathways that culminate in cell proliferation, cytokine secretion, chemokine gene expression, and cytolytic effector functions. Normal endothelial cells (EC) express low levels of CD44, but expression is up-regulated by activation with, for example, cytokines, and by culturing of these cells (7). Expression is also increased on the vasculature of solid tumors (7,8). Expression of CD44 on EC is associated with homing and migration of leukocytes (i.e., inflammation and migration). In addition, it has been demonstrated that CD44 plays some role in new blood vessel formation (angiogenesis), although its pre...

Cancer immunotherapy has evolved and is aimed at generating the efficacious therapeutic modality to enhance the specificity and power of the immune system to combat tumors. Areas covered: Current efforts in cancer immunotherapy fall into three main approaches. One approach is through the blockade of immune checkpoints, another approach is through adoptive cellular therapy, and the last approach is through vaccination. The goal of this review is to summarize the current understanding and status of cancer immunotherapy in these three categories. Expert commentary: We foresee the development of therapeutic protocols combining these approaches with each other or conventional therapies to achieve the most appropriate guideline for management of cancer.

Vascular endothelial cell growth factor (VEGF) stimulates endothelial cell (EC) proliferation and migration and mediates vascular growth and angiogenesis through two receptors, VEGFR‐1 (Flt‐1) and VEGFR‐2 (KDR). Similar biological activity has been attributed to cyclooxygenase (COX)‐1 and ‐2, particularly in the angiogenic response to colon cancer. VEGF165 (50 ng/ml for 3 h) increased the generation of 6‐keto‐PGF1α in EC (2.8±0.36 ng/ml vs. 0.69±0.08 ng/ml, P < 0.05; n=9), which was prevented by the specific COX‐2 inhibitor NS398 (0.7±0.5 ng/ml). VEGF also induced COX‐2 protein expression. Extended exposure to VEGF (8–10 h) leads to COX‐1 protein expression. A peptide derived from the third globular domain of the VEGFR‐2 consisting of residues 247–261 (1 μM–1 mM) inhibited VEGF‐induced 6‐keto‐PGF1α generation and COX induction. Prolonged exposure (7–9 h) of EC to VEGF induced cell proliferation that was inhibited by a combination of COX‐1 and ‐2 inhibitors (SC560 and NS398), suggesting that proliferation is dependent on both isoforms. The inhibitory effect of the combined inhibitors was also seen with aspirin and was reversed by the addition of the stable PGI2 analog iloprost but not by the PGE2 or PGH2 analogs dinoprostone or U46619. In an angiogenic assay, new blood vessel formation induced by VEGF over 14 days was blocked by COX‐1 inhibition. COX induction and prostaglandin formation are downstream effectors of VEGF‐dependent EC activation and angiogenesis.