Multiple Immune-Suppressive Mechanisms in Fibrolamellar Carcinoma

Abstract

Fibrolamellar carcinoma (FLC) is a rare type of liver cancer that affects adolescents and young adults. The most effective treatment for FLC is surgical resection, but no standardized systemic therapy exists for patients with recurrent or unresectable FLC. As a first step to understand the immune microenvironment of FLC, we investigated targetable immune-checkpoint pathways, PD-1, PD-L1, B7-H3, IDO-1, and LAG3, in relation to CD8 þ cytotoxic T-lymphocyte density. Thirty-two FLC tumor specimens were analyzed using IHC staining for PD-L1, CD8, PD-1, IDO, LAG3, and B7-H3. Sixty-three percent of FLC cases demonstrated membranous PD-L1 expression on tumor cells, and almost 70% of cases demonstrated PD-L1 þ tumor-infiltrating lymphocytes and tumor-associated macrophages (TIL/TAM). Myeloid-derived cells appeared to be a major component of PD-L1 þ tumor-infiltrating immune cells. Forty percent of the cases showed B7-H3 expression in the tumor zone, with 91% cases showing B7-H3 expression in TILs and TAMs. IDO and PD-1 expression was highest in the tumor interface zone. B7-H3 or IDO expression on tumor cells significantly correlated with higher CD8 þ T-cell density. In conclusion, a high proportion of FLC cases showed robust expression of PD-1, PD-L1, B7-H3, and IDO in an adaptive immune-resistance pattern. Our findings provide further basis for targeting these different immune-checkpoint axes in FLC.

Identification of immunological subtypes of hepatocellular carcinoma with expression profiling of immune-modulating genes

“…The four immune subtypes were validated by IHC in 72 HCC patients from South China. The results have shown the following: (i) there is an association between high B7-H3 expression and poor survival in HCC, which is consistent with previous reports [21][22][23][24]; (ii) B7-H3 expression is positively associated with CD8 expression and a Th1/IFNγ gene signature in HCC; and (iii) patients with B7-H3 low /CD8 high subtype are correlated with favorable survival in HCCs. Our findings support the view that, despite the limited efficiency of immunotherapy, the endogenous antitumor immune response is a critical factor for survival Figure 6.…”

“…To elucidate the clinical significance of the upregulated immune checkpoints, we analyzed the relationship between these genes and overall survival (OS) of HCC patients. The results show that only two genes are significantly associated with poor OS: CD276 (B7-H3) (P = 0.014, Figure 2A) and CD47 (P = 0.039, Figure 2B), consistent with previous reports [20][21][22][23][24][25]. All the others do not have a statistically significant relationship with survival ( Supplementary Figure 1).…”

“…B7-H3 is expressed in various tumor cells and tissues, and its high expression has been associated with poor prognosis in various cancers, including HCC [21][22][23][24]. However, these studies have only focus on B7-H3 expression and its relationship with survival, and none of them has analyzed both B7-H3 and CD8 expressions simultaneously.…”

“…Despite B7-H3 was originally characterized as a stimulator of T cells [37], growing evidence has indicted it may indeed be an inhibitor [37][38][39][40]. In human HCC, B7-H3 dominantly functions in a inhibitory manner in tumor immunity via decreasing T cell proliferation and IFNγ production and B7-H3 can also be induced as a consequence of an anti-tumor T cell response, suggesting an adaptive immune resistance [23,24]. Accordingly, the positive correlation between B7-H3 expression and CD8 expression or Th1/IFNγ gene signature in our study implies that compensatory B7-H3 upregulation in HCC is induced as a result of an anti-tumor T cell response and patients with different expression patterns of B7-H3/CD8 have significantly different survivals.…”

Molecular profiling and analysis of genetic aberrations aimed at identifying potential therapeutic targets in fibrolamellar carcinoma of the liver

“…Using immunohistochemistry to look for immune checkpoint targetable pathways in 32 tumor samples of FLC, PD-L1 was found to be expressed in tumor cells in approximately 63% of patients, and significant expression of B7-H3, PD-1, and IDO was noted both in tumor cells and in the tumor microenvironment. 35 Checkpoint inhibitors have been used anecdotally with no significant results to our knowledge. Potential combination therapy as used for patients with hepatocellular carcinoma would be worth exploring.…”