Epithelial ovarian, fallopian tube, and primary peritoneal cancer are the most lethal gynecological malignant neoplasms.¹ Although the survival benefits of optimal cytoreduction and primary platinum taxane–based chemotherapy have been well established in conjunction with mounting evidence supporting the role of poly-adenosine diphosphate ribose polymerase inhibitors for BRCA-mutated or homologous recombination deficient ovarian cancer, there remains a paucity of effective treatments providing durable response in recurrent disease. Traditional second-line chemotherapies achieve limited clinical benefit, with objective response rates (ORRs) ranging from 10% to 25% and with significant treatment-related toxic effects, highlighting an enormous unmet need for the development of novel therapies.

Epithelial ovarian cancer (EOC) often presents with metastases and ascites. Granulocytic myeloid–derived suppressor cells are an immature population that impairs antitumor immunity. Since suppressive granulocytes in the ascites of patients with newly diagnosed EOC were morphologically mature, we hypothesized that PMN were rendered suppressive in the tumor microenvironment (TME). Circulating PMN from patients were not suppressive but acquired a suppressor phenotype (defined as ≥1 log ₁₀ reduction of anti-CD3/CD28–stimulated T cell proliferation) after ascites supernatant exposure. Ascites supernatants (20 of 31 supernatants) recapitulated the suppressor phenotype in PMN from healthy donors. T cell proliferation was restored with ascites removal and restimulation. PMN suppressors also inhibited T cell activation and cytokine production. PMN suppressors completely suppressed proliferation in naive, central memory, and effector memory T cells and in engineered tumor antigen–specific cytotoxic T lymphocytes, while antigen-specific cell lysis was unaffected. Inhibition of complement C3 activation and PMN effector functions, including CR3 signaling, protein synthesis, and vesicular trafficking, abrogated the PMN suppressor phenotype. Moreover, malignant effusions from patients with various metastatic cancers also induced the C3-dependent PMN suppressor phenotype. These results point to PMN impairing T cell expansion and activation in the TME and the potential for complement inhibition to abrogate this barrier to antitumor immunity.

The most recent report from the Centers for Disease Control and Prevention estimates that 116 people in the United States die per day after an opioid overdose and that 40% of all deaths due to an opioid overdose involve a prescription opioid.¹ The number of deaths due to a prescription opioid overdose totaled an estimated 20 000 in 2015, and more than 4.5 million people in the United States misuse prescription opioids.² An executive report from the US Council of Economic Advisers estimated that the total economic burden of the opioid crisis in 2015 was $504.0 billion, or 2.8% of the gross domestic product.³ Given these statistics, the US federal government declared the opioid epidemic a public health emergency. Thus, all health care professionals are encouraged to take appropriate steps to decrease the number of opioids dispensed and monitor their misuse, abuse, and diversion.

Regulatory CD4⁺ T cell (Treg), a subset of tumor-infiltrating lymphocytes (TILs), are known to suppress anticancer immunity but its clinical relevance in human breast cancer remains unclear. In this study, we estimated the relative abundance of Tregs in breast cancer of multiple patient cohorts by using the xCell algorithm on bulk tumor gene expression data. In total, 5177 breast cancer patients from five independent cohorts (TCGA-BRCA, GSE96058, GSE25066, GSE20194, and GSE110590) were analyzed. Treg abundance was not associated with cancer aggressiveness, patient survival, or immune activity markers, but it was lower in metastatic tumors when compared to matched primary tumors. Treg was associated with a high mutation rate of TP53 genes and copy number mutations as well as with increased tumor infiltration of M2 macrophages and decreased infiltration of T helper type 1 (Th1) cells. Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) was significantly associated with low Treg abundance in triple negative breast cancer (TNBC) but not in ER-positive/Her2-negative subtype. High Treg abundance was significantly associated with high tumor expression of multiple immune checkpoint inhibitor genes. In conclusion, Treg abundance may have potential as a predictive biomarker of pCR after NAC in TNBC.

To uncover underlying mechanisms associated with failure of indoleamine 2,3-dioxygenase 1 (IDO1) blockade in clinical trials, we conducted a pilot, window-of-opportunity clinical study in 17 patients with newly diagnosed advanced high-grade serous ovarian cancer before their standard tumor debulking surgery. Patients were treated with the IDO1 inhibitor epacadostat, and immunologic, transcriptomic, and metabolomic characterization of the tumor microenvironment was undertaken in baseline and posttreatment tumor biopsies. IDO1 inhibition resulted in efficient blockade of the kynurenine pathway of tryptophan degradation and was accompanied by a metabolic adaptation that shunted tryptophan catabolism toward the serotonin pathway. This resulted in elevated nicotinamide adenine dinucleotide (NAD ⁺ ), which reduced T cell proliferation and function. Because NAD ⁺ metabolites could be ligands for purinergic receptors, we investigated the impact of blocking purinergic receptors in the presence or absence of NAD ⁺ on T cell proliferation and function in our mouse model. We demonstrated that A2a and A2b purinergic receptor antagonists, SCH58261 or PSB1115, respectively, rescued NAD ⁺ -mediated suppression of T cell proliferation and function. Combining IDO1 inhibition and A2a/A2b receptor blockade improved survival and boosted the antitumor immune signature in mice with IDO1 overexpressing ovarian cancer. These findings elucidate the downstream adaptive metabolic consequences of IDO1 blockade in ovarian cancers that may undermine antitumor T cell responses in the tumor microenvironment.

Recurrent ovarian cancer patients, especially those resistant to platinum, lack effective curative treatments. To address this, we conducted a phase 2 clinical trial (NCT02853318) combining pembrolizumab with bevacizumab, to increase T cell infiltration into the tumor, and oral cyclophosphamide, to reduce the number of regulatory T cells. The trial accrued 40 heavily pretreated recurrent ovarian cancer patients. The primary endpoint, progression free survival, was extended to a median of 10.2 months. The secondary endpoints demonstrated an objective response rate of 47.5%, and disease control in 30% of patients for over a year while maintaining a good quality of life. We performed comprehensive molecular, immune, microbiome, and metabolic profiling on samples of trial patients. Here, we show increased T and B cell clusters and distinct microbial patterns with amino acid and lipid metabolism are linked to exceptional clinical responses. This study suggests the immune milieu and host-microbiome can be leveraged to improve antitumor response in future immunotherapy trials.