BackgroundImmune checkpoint inhibitors, including antibodies against programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4), are being used with increasing frequency for the treatment of cancer. Immune-related adverse events (irAEs) including colitis, dermatitis, and pneumonitis are well described, but less frequent events are now emerging with larger numbers of patients treated. Herein we describe the incidence and spectrum of thrombocytopenia following immune checkpoint inhibitor therapy and two severe cases of idiopathic thrombocytopenic purpura (ITP).Case presentationsA 47-year-old female with recurrent BRAF mutant positive melanoma received combination anti-PD-1 and anti-CTLA-4. Two weeks later, she presented with mucosal bleeding, petechiae, and thrombocytopenia and was treated with standard therapy for ITP with steroids and intravenous immunoglobulin (IVIG). Her diagnosis was confirmed with bone marrow biopsy, and given the lack of treatment response, she was treated with rituximab. She began to have recovery and stabilization of her platelet count that ultimately allowed her to be retreated with PD-1 inhibition with no further thrombocytopenia. A second patient, a 45-year-old female with a BRAF wild-type melanoma, received anti-PD-1 monotherapy and became thrombocytopenic 43 days later. Three weeks of steroid treatment improved her platelet count, but thrombocytopenia recurred and required additional steroids. She later received anti-CTLA-4 monotherapy and developed severe ITP with intracranial hemorrhage. Her ITP resolved after treatment of prednisone, IVIG, and rituximab and discontinuation of checkpoint inhibition. In a retrospective chart review of 2360 patients with melanoma treated with checkpoint inhibitor therapy, <1% experienced thrombocytopenia following immune checkpoint inhibition, and of these, most had spontaneous resolution and did not require treatment.ConclusionsThrombocytopenia, especially ITP, induced by immune checkpoint inhibitors appears to be an uncommon irAE that is manageable with observation in mild cases and/or standard ITP treatment algorithms. In our series, the majority of patients had mild thrombocytopenia that resolved spontaneously or responded to standard corticosteroid regimens. However, in two severe cases, IVIG and rituximab, in addition to steroids, were required. Checkpoint inhibition was resumed successfully in the first patient but rechallenge was not tolerated by the second patient.

Malignant tumors reprogram cellular metabolism to support cancer cell proliferation and survival. Although most cancers depend on a high rate of aerobic glycolysis, many cancer cells also display addiction to glutamine. Mounting evidence indicates key roles of glutamine transporters and glutaminase activity in cancer glutamine metabolism. Here, we show that the EphA2 receptor tyrosine kinase activates YAP and TAZ (YAP/TAZ), transcriptional co-activators of the TEAD family of transcription factors, to promote glutamine metabolism in models of HER2-positive breast cancer. EphA2 overexpression induced nuclear accumulation of YAP and TAZ and increased expression of YAP/TAZ target genes. Inhibition of Rho or ROCK kinase abolished EphA2-dependent YAP/TAZ nuclear localization, suggesting Rho signaling as a critical intermediary. Silencing of YAP or TAZ significantly reduced intracellular glutamate, through differential regulation of SLC1A5 and GLS, respectively. Indeed, the regulatory DNA elements of both SLC1A5 and GLS contain TEAD binding sites and were bound by TEAD4 in an EphA2-dependent manner. In human breast cancer, EphA2 expression positively correlates with YAP and TAZ, as well as GLS and SLC1A5. While high expression of EphA2 predicts enhanced metastatic potential and poor survival, increased EphA2 expression rendered HER2-positive breast cancer cells more sensitive to glutaminase inhibition. Together, these findings define a novel mechanism of EphA2-mediated YAP/TAZ activation to promote glutaminolysis through upregulation of GLS and SLC1A5 in HER2+ breast cancer.

More than twenty-five years of research and pre-clinical validation have defined EphA2 receptor tyrosine kinase as a promising molecular target for clinical translation in cancer treatment. Molecular, genetic, biochemical, and pharmacological targeting strategies have been extensively tested in vitro and in vivo , and drugs like dasatinib, initially designed to target SRC family kinases, have been found to also target EphA2 activity. Other small molecules, therapeutic targeting antibodies, and peptide-drug conjugates are being tested, and more recently, approaches harnessing anti-tumor immunity against EphA2-expressing cancer cells have emerged as a promising strategy. This review will summarize pre-clinical studies supporting the oncogenic role of EphA2 in breast cancer, lung cancer, glioblastoma, and melanoma, while delineating the differing roles of canonical and noncanonical EphA2 signaling in each setting. This review also summarizes completed and ongoing clinical trials, highlighting the promise and challenges of targeting EphA2 in cancer.

The family of Eph receptor tyrosine kinases and their ephrin ligands regulate a diverse array of physiological processes, such as axonal guidance, bone remodeling, and immune cell development and trafficking. Eph/ephrin interactions have also been implicated in various pathological processes, including inflammation, cancer, and tumor angiogenesis. Because Eph receptors play prominent roles in both the immune system and cancer, they likely impact the tumor immune microenvironment, an area in which Eph receptors remain understudied. Here, we provide the first comprehensive review of Eph receptors in the context of tumor immunity. With the recent rise of cancer immunotherapies as promising therapeutic interventions, further elucidation of the roles of Eph receptors in the tumor immune microenvironment will be critical for understanding and developing novel targets against tumor immune evasion.

Background: Approximately 10% of patients with SCLC develop a paraneoplastic syndrome (PNS). Neurologic PNS are thought to improve prognosis, which we hypothesized is related to increased tumor-infiltrating lymphocytes and immune recognition. Methods: We queried 2,512,042 medical records from a single institution to identify patients who have SCLC with and without PNS and performed manual, retrospective chart review. We then performed multiplexed fluorescence immunohistochemistry and automated quantitative analysis (AQUA Technology) on tumors to assess CD3, CD4, and CD8 T cell infiltrates and programmed death 1 (PD-1)/ programmed death ligand 1 (PD-L1) interactions. T cell infiltrates and PD-1/PD-L1 interaction scores were compared among patients with neurologic PNS, endocrinologic PNS, and a control group without PNS. Clinical outcomes were analyzed using the Kaplan-Meier method and Cox proportional hazards models. Results: We evaluated 145 SCLC patients: 55 with PNS (25 neurologic and 30 endocrinologic) and 90 controls. Patients with neurologic PNS experienced improved overall survival compared to patients with endocrinologic PNS and controls (median overall survival of 24 months versus 12 months versus 13 months, respectively). Of the 145 patients, we identified tumor tissue from 34 patients that was adequate for AQUA analysis. Among 37 specimens from these 34 patients, patients with neurologic PNS had increased T cell infiltrates (p ¼ 0.033) and PD-1/PD-L1 interaction (p ¼ 0.014) compared to tumors from patients with endocrinologic PNS or controls. Conclusions: Tumor tissue from patients with SCLC with neurologic PNS showed increased tumor-infiltrating lymphocytes and PD-1/PD-L1 interaction consistent with an inflamed tumor microenvironment.

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Novel characterization of patterns of adverse events (AEs) of kinase inhibitors (KIs) could reveal new insights on human molecular physiology and methods to improve the therapeutic index of KIs. Incidence and severity of AEs for each of 157 patients enrolled in sorafenib clinical trials were determined for three clinically relevant treatment intervals: weeks 0–3, weeks 3–7, and after 7 weeks. The most common within patient co‐occurrences were mucositis with dermatologic events: hand‐foot syndrome (HFS; odds ratio [OR] = 4.36; p = 0.0017) and rash (OR = 5.32; p < 0.001). Prevalence of severe: alopecia (p = 0.02), diarrhea (p < 0.001), and fatigue (p = 0.005) increased over the course of therapy. Incidence of HFS (60%) and diarrhea (25%) increased up to a minimum steady‐state concentration (approximately 5 mcg mL‐1) and plateaued thereafter. Common AEs of sorafenib occur in distinct temporal and tissue distribution patterns and this analysis identified unrecognized relationships among mechanism‐dependent and independent effects of a KI.

Background: The conventional dogma of treating cancer by focusing on the elimination of tumor cells has been recently refined to include consideration of the tumor microenvironment, which includes host stromal cells. Ephrin-A1, a cell surface protein involved in adhesion and migration, has been shown to be tumor suppressive in the context of the cancer cell. However, its role in the host has not been fully investigated. Here, we examine how ephrin-A1 host deficiency affects cancer growth and metastasis in a murine model of breast cancer. Methods: 4T1 cells were orthotopically implanted into the mammary fat pads or injected into the tail veins of ephrin-A1 wild-type (Efna1+/+), heterozygous (Efna1+/-), or knockout (Efna1-/-) mice. Tumor growth, lung metastasis, and tumor recurrence after surgical resection were measured. Flow cytometry and immunohistochemistry (IHC) were used to analyze various cell populations in primary tumors and tumor-bearing lungs. Results: While primary tumor growth did not differ between Efna1+/+, Efna1+/-, and Efna1-/- mice, lung metastasis and primary tumor recurrence were significantly decreased in knockout mice. Efna1-/- mice had reduced lung colonization of 4T1 cells compared to Efna1+/+ littermate controls as early as 24 hours after tail vein injection. Furthermore, established lung lesions in Efna1-/- mice had reduced proliferation compared to those in Efna1+/+ controls. Conclusions: Our studies demonstrate that host deficiency of ephrin-A1 does not impact primary tumor growth but does affect metastasis by providing a less favorable metastatic niche for cancer cell colonization and growth. Elucidating the mechanisms by which host ephrin-A1 impacts cancer relapse and metastasis may shed new light on novel therapeutic strategies.