Purpose: We developed a novel systemic immune-inflammation index (SII) based on lymphocyte, neutrophil, and platelet counts and explored its prognostic value in hepatocellular carcinoma (HCC). Experimental Design: The SII was developed based on a retrospective study of 133 patients with HCC undergoing resection between 2005 and 2006, and validated in a prospective study of 123 patients enrolled from 2010 to 2011. The circulating tumor cell (CTC) level in the validation cohort was measured using the CellSearch system. Prediction accuracy was evaluated with area under the receiver operating characteristic curve (AUC). Results: An optimal cutoff point for the SII of 330 × 109 stratified the patients with HCC into high (≥330) and low SII (<330) groups in the training cohort. Univariate and multivariate analyses revealed the SII was an independent predictor for overall survival and relapse-free survival, and prognostic for patients with negative α-fetoprotein and Barcelona Clinic Liver Cancer stage 0+A. The AUCs of the SII for survival and recurrence were higher than other conventional clinical indices. An SII ≥ 330 was significantly associated with vascular invasion, large tumors, and early recurrence. CTC levels were significantly higher in the SII ≥ 330 group (1.71 ± 0.34 vs. 4.37 ± 1.04, P = 0.029). In patients with detectable CTCs, those with SII ≥ 330 had higher recurrence rates and shorter survival time than patients with SII < 330. Conclusion: The SII was a powerful prognostic indicator of poor outcome in patients with HCC and is a promising tool for HCC treatment strategy decisions. The dismal outcome in patients with high SII scores might be related to higher CTC levels. Clin Cancer Res; 20(23); 6212–22. ©2014 AACR.

Cancers rely on the tumor microenvironment, which comprises a variety of nonmalignant stromal cells for growth, invasion, and metastasis.¹ x 1 Zhou, S.L., Dai, Z., Zhou, Z.J. et al. CXCL5 contributes to tumor metastasis and recurrence of intrahepatic cholangiocarcinoma by recruiting infiltrative intratumoral neutrophils. Carcinogenesis. 2014; 35: 597–605 Crossref | PubMed | Scopus (40) | Google Scholar See all References ^{, 2} x 2 Quail, D.F. and Joyce, J.A. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013; 19: 1423–1437 Crossref | PubMed | Scopus (1358) | Google Scholar See all References Recent evidence has indicated that there is a complex and multidirectional interplay between tumor cells and immune or nonimmune stromal cells during cancer development and progression. The interaction between tumor and stromal cells may polarize stromal cells to favor tumor promotion.² x 2 Quail, D.F. and Joyce, J.A. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013; 19: 1423–1437 Crossref | PubMed | Scopus (1358) | Google Scholar See all References ^{, 3} x 3 Brandau, S., Dumitru, C.A., and Lang, S. Protumor and antitumor functions of neutrophil granulocytes. Semin Immunopathol. 2013; 35: 163–176 Crossref | PubMed | Scopus (63) | Google Scholar See all References Moreover, unlike tumor cells, stromal cells within the tumor microenvironment are genetically stable and represent an attractive therapeutic target because they are less likely to develop drug resistance.² x 2 Quail, D.F. and Joyce, J.A. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013; 19: 1423–1437 Crossref | PubMed | Scopus (1358) | Google Scholar See all References

The last 3 years have seen the emergence of promising targeted therapies for the treatment of hepatocellular carcinoma (HCC). Sorafenib has been the mainstay of treatment for a decade and newer modalities were ineffective and did not confer any increased therapeutic benefit until the introduction of lenvatinib which was approved based on its non-inferiority to sorafenib. The subsequent success of regorafenib in HCC patients who progress on sorafenib treatment heralded a new era of second-line treatment and was quickly followed by ramucirumab, cabozantinib, and the most influential, immune checkpoint inhibitors (ICIs). Over the same period combination therapies, including anti-angiogenesis agents with ICIs, dual ICIs and targeted agents in conjunction with surgery or other loco-regional therapies, have been extensively investigated and have shown promise and provided the basis for exciting clinical trials. Work continues to develop additional novel therapeutic agents which could potentially augment the presently available options and understand the underlying mechanisms responsible for drug resistance, with the goal of improving the survival of patients with HCC.

Hepatocellular carcinoma (HCC) is an immunotherapy-resistant malignancy characterized by high cellular heterogeneity. The diversity of cell types and the interplay between tumor and non-tumor cells remain to be clarified. Single cell RNA sequencing of human and mouse HCC tumors revealed heterogeneity of cancer-associated fibroblast (CAF). Cross-species analysis determined the prominent CD36 ⁺ CAFs exhibited high-level lipid metabolism and expression of macrophage migration inhibitory factor (MIF). Lineage-tracing assays showed CD36 ⁺ CAFs were derived from hepatic stellate cells. Furthermore, CD36 mediated oxidized LDL uptake-dependent MIF expression via lipid peroxidation/p38/CEBPs axis in CD36 ⁺ CAFs, which recruited CD33 ⁺ myeloid-derived suppressor cells (MDSCs) in MIF- and CD74-dependent manner. Co-implantation of CD36 ⁺ CAFs with HCC cells promotes HCC progression in vivo. Finally, CD36 inhibitor synergizes with anti-PD-1 immunotherapy by restoring antitumor T-cell responses in HCC. Our work underscores the importance of elucidating the function of specific CAF subset in understanding the interplay between the tumor microenvironment and immune system.