Search

Summary: Converting checkpoint inhibitor (CPI)-resistant individuals to being responsive requires identifying suppressive mechanisms. We identify TREM2+ tumor-associated macrophages (TAMs) as being correlated with exhausted CD8+ tumor-infiltrating lymphocytes (TILs) in mouse syngeneic tumor models and human solid tumors of multiple histological types. Fc domain-enhanced anti-TREM2 monoclonal antibody (mAb) therapy promotes anti-tumor immunity by elimination and modulation of TAM populations, which leads to enhanced CD8+ TIL infiltration and effector function. TREM2+ TAMs are most enriched in individuals with ovarian cancer, where TREM2 expression corresponds to disease grade accompanied by worse recurrence-free survival. In an aggressive orthotopic ovarian cancer model, anti-TREM2 mAb therapy drives potent anti-tumor immunity. These results highlight TREM2 as a highly attractive target for immunotherapy modulation in individuals who are refractory to CPI therapy and likely have a TAM-rich tumor microenvironment.

ABSTRACT: BACKGROUND: A bioinformatics approach identified antitumor effects of tricyclic antidepressants (TCAs) in small cell lung cancer (SCLC) and other high-grade neuroendocrine carcinomas (grade 3 neuroendocrine carcinomas) (G3NEC) that was subsequently validated in preclinical models with a putative mechanism of action via inhibition of neuroendocrine signaling pathways. This study was undertaken to reposition the candidate TCA desipramine in a clinical trial in SCLC and G3NEC. METHODS: In this prospective, phase IIa intrapatient dose escalation clinical trial, patients were required to have failed at least one prior chemotherapy for metastatic SCLC or G3NEC. Treatment with desipramine began at 75 mg nightly with escalation in increments of 75 mg weekly to a maximum of 450 mg daily. RESULTS: Six patients were enrolled, 3 with SCLC, and 3 with G3NEC (lung, rectal, and pancreas). Tolerability of desipramine was worse than predicted. Of the 6 patients enrolled: 1 patient achieved 300 mg daily, 2 patients reached 150 mg daily, 1 patient reached 75 mg daily, and 2 patients were unable to tolerate any stable dose. Reasons for discontinuation included drug-related grade 3 colon pseudo-obstruction, unrelated GI bleed, and grade 1-2 neurocognitive adverse events. Median clinical or radiographic progression free survival was 1.2 months (range 0.2-3.3) and median overall survival from study entry was 2.7 months (range 1.3-5.6). CONCLUSIONS: No clinical or radiographic benefit was observed using desipramine to treat SCLC and G3NEC, so this trial was terminated. Intolerable low and medium grade neurocognitive side effects led to intermittent treatment and early discontinuation in most patients; given this limitation, doses achieved may be inadequate compared to the preclinical studies. MICROABSTRACT: A bioinformatics approach previously identified a potential antitumor effect of tricyclic antidepressants (TCAs) in small cell lung cancer (SCLC) and other high-grade neuroendocrine carcinomas (grade 3 neuroendocrine carcinoma) (G3NEC), which was validated in preclinical models.In this prospective, phase IIa clinical trial, patients were required to have failed at least one prior chemotherapy for metastatic SCLC or G3NEC (Ki-67 ≥ 20% or ≥ 20 mitoses/10 HPF). Treatment with desipramine began at 75 mg nightly with escalation by 75 mg weekly to a maximum dose of 450 mg daily. Six patients were enrolled on this clinical trial, 3 with SCLC, and 3 with G3NEC (lung, rectal, and pancreatic). Tolerability of desipramine was worse than predicted. In the 6 patients enrolled: 1 patient achieved 300 mg daily, 2 patients reached 150 mg daily, 1 patient reached 75 mg daily, and 2 patients were unable to tolerate any stable dose. Reasons for discontinuation included drug-related grade 3 colon pseudo-obstruction, unrelated GI bleed, and grade 1-2 drug related dizziness, confusion, and somnolence. Though numbers are small, median clinical or radiographic progression free survival was 1.2 months (range 0.2-3.3) and median overall survival from study entry was 2.7 months (range 1.3-5.6). Although preclinical evidence was promising, no clinical or radiographic benefit was observed using desipramine to treat SCLC and G3NEC, so this trial was terminated.

The tumor microenvironment (TME) of diverse cancer types is often characterized by high levels of infiltrating myeloid cells including monocytes, macrophages, dendritic cells, and granulocytes. These cells perform a variety of functions in the TME, varying from immune suppressive to immune stimulatory roles. In this review, we summarize the different myeloid cell populations in the TME and the intratumoral myeloid targeting approaches that are being clinically investigated, and discuss strategies that identify new myeloid subpopulations within the TME. The TME therapies include agents that modulate the functional activities of myeloid populations, that impact recruitment and survival of myeloid subpopulations, and that functionally reprogram or activate myeloid populations. We discuss the benefits, limitations and potential side effects of these therapeutic approaches.

Small cell lung cancer (SCLC) is a neuroendocrine lung cancer characterized by fast growth, early dissemination, and rapid resistance to chemotherapy. We identified a population of long-term tumor-propagating cells (TPCs) in a mouse model of SCLC. This population, marked by high levels of EpCAM and CD24, is also prevalent in human primary SCLC tumors. Murine SCLC TPCs are numerous and highly proliferative but not intrinsically chemoresistant, indicating that not all clinical features of SCLC are linked to TPCs. SCLC TPCs possess a distinct transcriptional profile compared to non-TPCs, including elevated MYC activity. Genetic and pharmacological inhibition of MYC in SCLC cells to non-TPC levels inhibits long-term propagation but not short-term growth. These studies identify a highly tumorigenic population of SCLC cells in mouse models, cell lines, and patient tumors and a means to target them in this most fatal form of lung cancer.

SnoN is a negative regulator of TGF-β signaling and also an activator of the tumor suppressor p53 in response to cellular stress. Its role in human cancer is complex and controversial with both pro-oncogenic and anti-oncogenic activities reported. To clarify its role in human cancer and provide clinical relevance to its signaling activities, we examined SnoN expression in normal and cancerous human esophageal, ovarian, pancreatic and breast tissues. In normal tissues, SnoN is expressed in both the epithelium and the surrounding stroma at a moderate level and is predominantly cytoplasmic. SnoN levels in all tumor epithelia examined are lower than or similar to that in the matched normal samples, consistent with its anti-tumorigenic activity in epithelial cells. In contrast, SnoN expression in the stroma is highly upregulated in the infiltrating inflammatory cells in high-grade esophageal and ovarian tumor samples, suggesting that SnoN may potentially promote malignant progression through modulating the tumor microenvironment in these tumor types. The overall levels of SnoN expression in these cancer tissues do not correlate with the p53 status. However, in human cancer cell lines with amplification of the snoN gene, a strong correlation between increased SnoN copy number and inactivation of p53 was detected, suggesting that the tumor suppressor SnoN-p53 pathway must be inactivated, either through downregulation of SnoN or inactivation of p53, in order to allow cancer cell to proliferate and survive. These data strongly suggest that SnoN can function as a tumor suppressor at early stages of tumorigenesis in human cancer tissues.