Tumor-associated macrophages (TAMs) usually display an antiinflammatory M2-like phenotype to facilitate tumor growth. However, what drives M2 polarization of TAMs and how TAMs suppress antitumor immunity within the tumor microenvironment (TME) remain largely undefined. Using several murine tumor models, we showed that hedgehog (Hh) signaling in myeloid cells is critical for TAM M2 polarization and tumor growth. We also found that tumor cells secrete sonic hedgehog (SHH), an Hh ligand, and that tumor-derived SHH drives TAM M2 polarization. Furthermore, Hh-induced functional polarization in TAMs suppresses CD8+ T cell recruitment to the TME through the inhibition of CXCL9 and CXCL10 production by TAMs. Last, we demonstrated that Krüppel-like factor 4 (Klf4) mediates Hh-dependent TAM M2 polarization and the immunosuppressive function. Collectively, these findings highlight a critical role for tumor-derived SHH in promoting TAM M2 polarization, a mechanism for TAM-mediated immunosuppression, and may provide insights into the design of new cancer immunotherapeutic strategies.

The programmed death-1 (PD-1) and the PD ligand 1 (PD-L1) interaction represents a key immune checkpoint within the tumor microenvironment (TME), and PD-1 blockade has led to exciting therapeutic advances in clinical oncology. Although IFN-γ–dependent PD-L1 induction on tumor cells was initially thought to mediate the suppression on effector cells, recent studies have shown that PD-L1 is also expressed at high level on tumor-associated macrophages (TAMs) in certain types of tumors. However, the precise role of PD-L1 expression on TAMs in suppressing antitumor immunity within the TME remains to be defined. Using a myeloid-specific Pdl1 -knockout mouse model, here we showed definitive evidence that PD-L1 expression on TAMs is critical for suppression of intratumor CD8 ⁺ T cell function. We further demonstrated that tumor-derived Sonic hedgehog (Shh) drives PD-L1 expression in TAMs to suppress tumor-infiltrating CD8 ⁺ T cell function, leading to tumor progression. Mechanistically, Shh-dependent upregulation of PD-L1 in TAMs is mediated by signal transducer and activator of transcription 3, a cascade that has not been previously reported to our knowledge. Last, single-cell RNA sequencing analysis of human hepatocellular carcinoma revealed that PD-L1 is mainly expressed on M2 TAMs, supporting the clinical relevance of our findings. Collectively, our data revealed an essential role for Shh-dependent PD-L1 upregulation in TAMs in suppressing antitumor immunity within the TME, which could lead to the development of new immunotherapeutic strategies for treating cancer.

Cells are fundamental units of life, but little is known about evolution of cell states. Induced pluripotent stem cells (iPSCs) are once differentiated cells that have been re-programmed to an embryonic stem cell-like state, providing a powerful platform for biology and medicine. However, they have been limited to a few mammalian species. Here we found that a set of four mammalian transcription factor genes used to generate iPSCs in mouse and humans can induce a partially reprogrammed pluripotent stem cell (PRPSCs) state in vertebrate and invertebrate model organisms, in mammals, birds, fish, and fly, which span 550 million years from a common ancestor. These findings are one of the first to show cross-lineage stem cell-like induction, and to generate pluripotent-like cells for several of these species with in vivo chimeras. We suggest that the stem-cell state may be highly conserved across a wide phylogenetic range.

Traditionally considered a disease common in the older population, colorectal cancer is increasing in incidence among younger demographics. Evidence suggests that populational- and generational-level shifts in the composition of the human gut microbiome may be tied to the recent trends in gastrointestinal carcinogenesis. This review provides an overview of current research and putative mechanisms behind the rising incidence of colorectal cancer in the younger population, with insight into future interventions that may prevent or reverse the rate of early-onset colorectal carcinoma.

Pluripotent stem cells have the potential to become any cell in the adult body, including neurons and glia. Avian stem cells could be used to study questions, like vocal learning, that would be difficult to examine with traditional mouse models. Induced pluripotent stem cells (iPSCs) are differentiated cells that have been reprogrammed to a pluripotent stem cell state, usually using inducing genes or other molecules. We recently succeeded in generating avian iPSC-like cells using mammalian genes, overcoming a limitation in the generation and use of iPSCs in nonmammalian species (Rosselló et al., 2013). However, there were no established optimal cell culture conditions for avian iPSCs to establish long-term cell lines and thus to study neuronal differentiationin vitro. Here we present an efficient method of maintaining chicken iPSC-like cells and for differentiating them into action potential generating neurons.

Rationale: Giant ovarian tumors are very rare. Patients with large ovarian tumors appear similar to pregnant women and morbidly obese patients. The management of such patients is associated with significant mortality. Therefore, additional clinical research is essential to understanding the perioperative complications of this disease. Patient concerns: We report the perioperative management of a patient with a giant ovarian tumor that contained 23 L of fluid who underwent tumor resection. Given the infrequency of these giant ovarian tumors, a detailed anesthetic plan and postoperative respiratory support strategy were tailored to address the patient's hemodynamic and respiratory risks, as well as to minimize potential complications, including supine hypotensive syndrome, re-expansion pulmonary edema, and postoperative intestinal ileus. To prevent supine hypotensive syndrome, the patient used a mild left-sided position (10∼20°) after admission until the tumor was removed. In order to prevent re-expansion pulmonary edema (RPE), the intraoperative ventilator mode was set to pressure-controlled ventilation (PCV), with the addition of 8 cmH₂O positive end-expiratory pressure (PEEP). The airway pressure was lower while maintaining a certain tidal volume. In the ICU, in the ventilator mode, we use pressure support ventilation as well as PEEP and adjust it according to the patient's spontaneous breathing situation and blood gas analysis to prepare for further detach from the respirator and extubation. And we prevent the occurrence of postoperative intestinal ileus by placing the abdominal binder after the operation. Diagnosis: Mucinous cystadenoma of the left ovary. Interventions: The patient underwent exploratory laparotomy with debulking of the left ovarian mass, transabdominal hysterectomy with bilateral salpingo-oophorectomy, complete omentectomy with appendectomy, and pelvic lymphadenectomy. Outcomes: After surgery, the patient experienced intestinal distention. Up to now, the patient has recovered well. Lessons: A multidisciplinary approach is essential. Knowing the possibility of complications and choices for management can lead to favorable outcomes in such rare cases. This case reminds us that postoperative complications such as postoperative intestinal ileus may be fatal.