Autoimmunity affecting the biliary tract fuels the immunosurveillance of cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA) results from the malignant transformation of cholangiocytes. Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are chronic diseases in which cholangiocytes are primarily damaged. Although PSC is an inflammatory condition predisposing to CCA, CCA is almost never found in the autoimmune context of PBC. Here, we hypothesized that PBC might favor CCA immunosurveillance. In preclinical murine models of cholangitis challenged with syngeneic CCA, PBC (but not PSC) reduced the frequency of CCA development and delayed tumor growth kinetics. This PBC-related effect appeared specific to CCA as it was not observed against other cancers, including hepatocellular carcinoma. The protective effect of PBC was relying on type 1 and type 2 T cell responses and, to a lesser extent, on B cells. Single-cell TCR/RNA sequencing revealed the existence of TCR clonotypes shared between the liver and CCA tumor of a PBC host. Altogether, these results evidence a mechanistic overlapping between autoimmunity and cancer immunosurveillance in the biliary tract.

Beneficial autoimmunity links primary biliary cholangitis to the avoidance of cholangiocarcinoma

“…Depletion of T cells (by injections of antibodies specific to CD4 and CD8), elimination of B cells (by anti-CD20) or neutralization of IFNγ or IL4 (but not that of IL17) by means of suitable neutralizing antibodies, accelerated the growth of CCA effects post-PBC, yet did not affect CCA progression in control or PSC mice. 3 The aforementioned results strongly suggest that PBC induces an autoimmune response that cross-reacts against CCA, hence specifically enhancing immunosurveillance against this specific cancer type. To obtain formal proof in favor of this conjecture, we used single-cell RNA-seq and single-cell TCR sequencing to compare T lymphocytes purified from PBC livers, peripheral blood and CCA tumors.…”

“…This infiltration pattern of PBC was corroborated by cytometry-based immunophenotyping. 3 Of note, a CCA cell line that was injected subcutaneously in control mice or mice with PSC developed tumors indistinguishably in healthy control mice and animals with PSC. In sharp contrast, such CCAs either failed to develop palpable tumors or grew more slowly in mice with PBC.…”

“…Moreover, it extended to orthotopic cholangiocarcinogenesis (induced by hydrodynamic injection of oncogene-expressing vectors) that was prevented upon PBC as opposed to control mice without cholangitis. 3 The transplantable CCAs that slowly developed on mice with PBC exhibited a more favorable ratio of tumorinfiltrating CD8 + cytotoxic T lymphocytes (CTLs) over FoxP3 + regulatory CD4 + T cells (Tregs) than CCAs growing in control mice or in the context of PSC. Moreover, in the context of PBC, CCA tumor-draining lymph nodes contained higher levels of granzyme B-positive T cells producing several cytokines (such as IFNγ, IL2, IL4, IL-17 and TNFα) than in CCA-bearing mice without cholangitis or post-PSC.…”

“…We found that, in the same mouse with PBC, a substantial proportion of CCA-infiltrating and intrahepatic CD4 + and CD8 + T cells shared identical TCRs (Figure 1C), strongly suggesting that T cells that recognize PBCrelevant autoantigens also recognize CCA. 3 Circumstantial evidence suggests that immune responses against antigens expressed by normal, non-transformed cells can contribute to anticancer immunosurveillance. For example, the CTL/Treg ratio detectable in normal, nonmalignant breast tissue, predicts the risk to develop breast cancer in spite of the surgical removal of ductal in situ carcinomas.…”

Beneficial autoimmunity and maladaptive inflammation shape epidemiological links between cancer and immune-inflammatory diseases

“…In specific conditions, autoimmune diseases have been linked to improved immunosurveillance, as exemplified for autoimmune thyroiditis and thyroid cancer, 9 , 10 vitiligo and melanoma 11 , 12 or non-cirrhotic primary biliary cholangitis and cholangiocarcinoma. 13 Moreover, in preclinical models, vaccination with normal epithelial cells from the intestine or the mammary gland can induce protective immune responses against colon and breast cancer, respectively, underscoring the possibility that immune responses against (by definition) non-mutated self-antigens can participate to cancer immunosurveillance. 14 , 15 The development of human breast cancer becomes also more improbable when histologically normal mammary gland is infiltrated by T lymphocytes at a high CD8/FOXP3 ratio, 16 pleading in favor of the hypothesis that even healthy tissues are patrolled by specific T cells to avoid their cancerization.…”