Incorporation of immunotherapy into the treatment of metastatic neuroendocrine carcinoma of the cervix: A case report.

•Ideal treatment for advanced neuroendocrine carcinoma of the cervix (NECC) remains unclear.•A patient with metastatic NECC experienced a durable complete response to multi-modal therapy that included atezolizumab.•Atezolizumab may improve response rates and overall survival when incorporated into therapy for NECC.

MYC Overexpression Drives Immune Evasion in Hepatocellular Carcinoma That Is Reversible through Restoration of Proinflammatory Macrophages.

Cancers evade immune surveillance, which can be reversed through immune-checkpoint therapy in a small subset of cases. Here, we report that the MYC oncogene suppresses innate immune surveillance and drives resistance to immunotherapy. In 33 different human cancers, MYC genomic amplification and overexpression increased immune-checkpoint expression, predicted nonresponsiveness to immune-checkpoint blockade, and was associated with both Th2-like immune profile and reduced CD8 T-cell infiltration. MYC transcriptionally suppressed innate immunity and MHCI-mediated antigen presentation, which in turn impeded T-cell response. Combined, but not individual, blockade of PDL1 and CTLA4 could reverse MYC-driven immune suppression by leading to the recruitment of proinflammatory antigen-presenting macrophages with increased CD40 and MHCII expression. Depletion of macrophages abrogated the antineoplastic effects of PDL1 and CTLA4 blockade in MYC-driven hepatocellular carcinoma (HCC). Hence, MYC is a predictor of immune-checkpoint responsiveness and a key driver of immune evasion through the suppression of proinflammatory macrophages. The immune evasion induced by MYC in HCC can be overcome by combined PDL1 and CTLA4 blockade. SIGNIFICANCE: Macrophage-mediated immune evasion is a therapeutic vulnerability of MYC-driven cancers, which has implications for prioritizing MYC-driven hepatocellular carcinoma for combination immunotherapy.

Implications of genetic heterogeneity in hepatocellular cancer.

Hepatocellular carcinoma (HCC) exhibits a remarkable degree of heterogeneity, not only at an inter-patient level but also between and within tumors in the same patient. The advent of next-generation sequencing (NGS)-based technologies has allowed the creation of high-resolution atlases of HCC. This review outlines recent findings from genomic, epigenomic, transcriptomic, and proteomic sequencing that have yielded valuable insights into the spatial and temporal heterogeneity of HCC. The high heterogeneity of HCC has both clinical and therapeutic implications. The challenges in prospectively validating molecular classifications for HCC either for prognostication or for prediction of therapeutic response are partly due to the immense heterogeneity in HCC. Moreover, the heterogeneity of HCC tumors combined with the lack of commonly mutated, druggable targets severely limits treatment options for HCC. Recently, immune checkpoint inhibitors and combination therapies have shown promise for advanced HCC, while T cell therapies and vaccines are currently being investigated. Yet, immunotherapies show benefit only in a limited subset of patients, making it imperative to decipher tumor heterogeneity in HCC in order to enable optimal patient selection. This review summarizes the cutting-edge research on heterogeneity in HCC and explores the implications of heterogeneity on stratifying patients and developing biomarkers and therapies for HCC.