Cancer progression is associated with alterations of intra- and extramedullary hematopoiesis to support a systemic tumor-promoting myeloid response. However, the functional specialty, mechanism, and clinical relevance of extramedullary hematopoiesis (EMH) remain unclear. Here, we showed that the heightened splenic myelopoiesis in tumor-bearing hosts was not only characterized by the accumulation of myeloid precursors, but also associated with profound functional alterations of splenic early hematopoietic stem/progenitor cells (HSPCs). With the distinct capability to produce and respond to granulocyte-macrophage CSF (GM-CSF), these splenic HSPCs were “primed” and committed to generating immunosuppressive myeloid cells. Mechanistically, the CCL2/CCR2 axis–dependent recruitment and the subsequent local education by the splenic stroma were critical for eliciting this splenic HSPC response. Selective abrogation of this splenic EMH was sufficient to synergistically enhance the therapeutic efficacy of immune checkpoint blockade. Clinically, patients with different types of solid tumors exhibited increased splenic HSPC levels associated with poor survival. These findings reveal a unique and important role of splenic hematopoiesis in tumor-associated myelopoiesis.

The combination of lenvatinib, toripalimab and hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) suggested encouraging antitumour activity in our retrospective study. We hereby prospectively establish the efficacy, safety and predictive biomarkers of the combination therapy as a first-line treatment in patients with high-risk advanced hepatocellular carcinoma (HCC). This phase II, single-centre, single-arm trial enrolled advanced HCC participants with high-risk. Of 51 screened participants, 36 received lenvatinib, toripalimab plus FOLFOX-HAIC. Participants received 21-day treatment cycles of lenvatinib, toripalimab, and FOLFOX-HAIC. The primary end-point was the progression-free survival (PFS) rate per RECIST at six months. Thirty-six participants (86.1% with high-risk features) were enrolled in our study. The primary end-point was met with a PFS rate of 80.6% (95% CI, 64.0%-91.8%) at six months. The median PFS was 10.4 months (95% CI, 5.8-15.0), and the median OS was not reached at the prespecified final analysis and was 17.9 months (95% CI, 14.5-21.3) after follow-up was extended. The ORR per RECIST was 63.9%, and per mRECIST was 66.7%. The median duration of response was 14.4 months (95% CI, 8.9-19.9). The most common adverse events were thrombocytopenia, elevated aspartate aminotransferase, and hypertension, and no treatment-related death was reported. Participants with low levels of both CCL28 and BTC had unsatisfactory prognosis. Lenvatinib, toripalimab and FOLFOX-HAIC showed safe and encouraging antitumour activity for advanced HCC with high-risk features. The levels of CCL28 and BTC might be the predictive biomarkers for the triple combination therapy.

Background: The long-term survival of patients with hepatocellular carcinoma (HCC) with portal vein tumour thrombus (PVTT) is poor. Systemic therapy, transcatheter arterial chemoembolization (TACE), and hepatic artery infusion chemotherapy are widely used in HCC patients with PVTT. This study aims to explore the efficacy of combining systemic therapy with transarterial-based therapy in HCC patients with PVTT. Materials and methods: The authors retrospectively reviewed data of HCC patients with PVTT treated with combination therapy (TACE-hepatic artery infusion chemotherapy with tyrosine kinase inhibitors and PD-1 inhibitors) or TACE alone in SYSUCC from 2011 to 2020. The overall survival (OS), progression-free survival, and overall response rate were compared. Propensity score matching was used to minimize confounding bias. Results: A total of 743 HCC patients with PVTT received combination therapy (n=139) or TACE alone (n=604). After propensity score matching, the overall response rate was significantly higher in the combination group than in the TACE group [42.1% vs. 5.0%, P < 0.001 (response evaluation criteria in solid tumours); 53.7% vs. 7.8%, P < 0.001 (modified response evaluation criteria in solid tumours)]. The combination group showed significantly better OS than the TACE group (median OS not reached vs. 10.4 months, P < 0.001). The median progression-free survival of the combination and TACE groups was 14.8 and 2.3 months (P < 0.001), respectively. Tumour downstaging followed by salvage liver resection was significantly more common for the combination therapy group than for TACE group (46.3% vs. 4.5%, P < 0.001). After salvage liver resection, 31.6% (30/95) and 1.7% (3/179) of the patients achieved a pathological complete response in the combination and TACE groups, respectively (P < 0.001). The grade 3/4 adverse events rates were similar between the two groups (28.1% vs. 35.9%, P=0.092). Conclusion: Compared with TACE alone, combination therapy was safe enough and resulted in survival benefits. This is a promising treatment option for HCC patients with PVTT.

Background: The optimal strategy for adjuvant therapy after curative resection for hepatocellular carcinoma (HCC) patients with solitary tumor and microvascular invasion (MVI) is controversial. This trial evaluated the efficacy and safety of adjuvant transcatheter arterial chemoembolization (TACE) after hepatectomy versus hepatectomy alone in HCC patients with a solitary tumor ≥ 5 cm and MVI. Methods: In this randomized, open‐labeled, phase III trial, HCC patients with a solitary tumor ≥ 5 cm and MVI were randomly assigned (1:1) to receive either 1–2 cycles of adjuvant TACE after hepatectomy (Hepatectomy‐TACE) or hepatectomy alone (Hepatectomy Alone). The primary endpoint was disease‐free survival (DFS); the secondary endpoints included overall survival (OS) and adverse events. Results: Between June 1, 2009, and December 31, 2012, 250 patients were enrolled and randomly assigned to the Hepatectomy‐TACE group ( n = 125) or the Hepatectomy Alone group ( n = 125). Clinicopathological characteristics were balanced between the two groups. The median follow‐up time from randomization was 37.5 months [interquartile range 18.3–48.2 months]. The median DFS was significantly longer in the Hepatectomy‐TACE group than in the Hepatectomy Alone group [17.45 months (95% confidence interval [CI] 11.99–29.14) vs. 9.27 months (95% CI 6.05–13.70), hazard ratio [HR] = 0.70 (95% CI 0.52–0.95), P = 0.020], respectively. The median OS was also significantly longer in the Hepatectomy‐TACE group than in the Hepatectomy Alone group [44.29 months (95% CI 25.99–62.58) vs. 22.37 months (95% CI 10.84–33.91), HR = 0.68 (95% CI 0.48–0.97), P = 0.029]. Treatment‐related adverse events were more frequently observed in the Hepatectomy‐TACE group, although these were generally mild and manageable. The most common grade 3 or 4 adverse events in both groups were neutropenia and liver dysfunction. Conclusion: Hepatectomy followed by adjuvant TACE is an appropriate option after radical resection in HCC patients with solitary tumor ≥ 5 cm and MVI, with acceptable toxicity.