Immunotherapy of hepatocellular carcinoma

Pardee, Angela D.; Butterfield, Lisa H.

doi:10.4161/onci.1.1.18344

Cited by 137 publications

(67 citation statements)

References 77 publications

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“…Late tumor development is associated with immunotolerance, tumor cell migration to DLNs, CTCs in the bloodstream, an increase of Tregs and MDSCs, and dysregulation of immune checkpoints, which mimick the clinical scenario of human HCC. As widely recognized human HCC associated antigens, the prominent expression of AFP and GPC3 in this model provides clinically relevant targets to advance immunotherapeutic translational studies[40-43]. We also optimized MRI parameters to monitor tumor growth in mice from a very early stage.…”

Section: Discussionmentioning

confidence: 99%

Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model

Dai

Cooper

et al. 2017

Journal of Hepatology

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Background and Aims We have established a clinically relevant animal model of hepatocellular cancer (HCC) in immune competent mice to elucidate the complex dialog between host immunity and tumors during HCC initiation and progression. Mechanistic findings have been leveraged to develop a clinically feasible antitumor chemoimmunotherapeutic strategy. Methods Intraperitoneal injection of carbon tetrachloride and intrasplenic inoculation of oncogenic hepatocytes were combined to induce progressive HCCs in fibrotic livers of immunocompetent mice. Immunization and adoptive cell transfer (ACT) were used to dissect the tumor antigen-specific immune response. The ability of the tyrosine kinase inhibitor sunitinib to enhance immunotherapy in the setting of HCC was evaluated. Results This new mouse model mimics human HCC and reflects its typical features. Tumor-antigen-specific CD8+ T cells maintained a naïve phenotype and remained responsive during early-stage tumor progression. Late tumor progression produced circulating tumor cells, tumor migration into draining lymph nodes, and profound exhaustion of tumor-antigen-specific CD8+ T cells associated with accumulation of PD-1hi CD8+ T cells and regulatory T cells (Tregs). Sunitinib-mediated tumoricidal effect and Treg suppression synergized with antibody-mediated blockade of PD-1 to powerfully suppress tumor growth and activate anti-tumor immunity. Conclusion Treg accumulation and upregulation of PD-1 provide two independent mechanisms to induce profound immune tolerance in HCC. Chemoimmunotherapy using FDA-approved sunitinib with anti-PD-1 antibodies achieved significant tumor control, supporting translation of this approach for the treatment of HCC patients.

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Section: Discussionmentioning

confidence: 99%

Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model

Dai

Cooper

et al. 2017

Journal of Hepatology

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“…While a minority of patients is eligible for curative surgery or transplantation, many patients will recur. Immunologically, the liver is a tolerogenic organ [26] with inherently non-stimulatory antigen presentation function. HCC patients also exhibit significant systemic immune suppression.…”

Section: Discussionmentioning

confidence: 99%

Lessons learned from cancer vaccine trials and target antigen choice

Butterfield

2016

Cancer Immunol Immunother

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A wide variety of tumor antigens have been targeted in cancer immunotherapy studies. Traditionally, the focus has been on commonly over-expressed antigens shared across many patients and/or tumor types. As the field has progressed, the identity of human tumor rejection antigens has broadened. Immunologic monitoring of clinical trials has slowly elucidated candidate biomarkers of immune response and clinical response, and conversely, of immune dysfunction and suppression. We have utilized MART-1/Melan-A in our melanoma studies, and observed a high frequency of immune responses and several significant clinical responses in patients vaccinated with this melanosomal protein. Alpha-fetoprotein (AFP) is a shared, over-expressed tumor antigen and secreted glycoprotein that we have tested in hepatocellular cancer (HCC) vaccines. Our recent studies have identified immune suppressive and immune skewing activities of this antigen. The choice of target antigen and its form can have unexpected effects.

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“…Based on its immunosuppressive properties, recombinant AFP is under development for the treatment of autoimmune diseases (41). In the setting of AFP-expressing cancers, namely HCC, AFP serves as an attractive target for immunotherapy, and several groups have investigated the anti-cancer potential of HCC tumor lysate- or AFP-based vaccines (16, 42, 43). Our data suggest that caution must be applied in the formulation of these therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Tumor-Derived α-Fetoprotein Impairs the Differentiation and T Cell Stimulatory Activity of Human Dendritic Cells

Pardee

Shi

Butterfield

2014

The Journal of Immunology

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Several tumor-derived factors have been implicated in DC dysfunction in cancer patients. Alpha-fetoprotein (AFP) is an oncofetal antigen that is highly expressed in abnormalities of prenatal development and several epithelial cancers, including hepatocellular carcinoma (HCC). In HCC patients exhibiting high levels of serum AFP, we have observed a lower ratio of myeloid-to-plasmacytoid circulating DC compared to patients with low serum AFP levels and healthy donors. To test the effect of AFP on DC differentiation in vitro, peripheral blood monocytes from healthy donors were cultured in the presence of cord blood-derived normal AFP (nAFP) or HCC tumor-derived AFP (tAFP), and DC phenotype and function was assessed. Although the nAFP and tAFP isoforms only differ at one carbohydrate group, low (physiological) levels of tAFP, but not nAFP, significantly inhibited DC differentiation. tAFP-conditioned DC expressed diminished levels of DC maturation markers, retained a monocyte-like morphology, exhibited limited production of inflammatory mediators, and failed to induce robust T cell proliferative responses. Mechanistic studies revealed that the suppressive activity of tAFP is dependent on the presence of low molecular weight (LMW) species that i) co-purify with tAFP, and ii) function equivalently to the LMW fractions of both tumor and non-tumor cell lysates. These data reveal the unique ability of tAFP to serve as a chaperone protein for LMW molecules, both endogenous and ubiquitous in nature, which function cooperatively to impair DC differentiation and function. Therefore, novel therapeutic approaches that antagonize the regulatory properties of tAFP will be critical to enhance immunity and improve clinical outcomes.

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Immunotherapy of hepatocellular carcinoma

Cited by 137 publications

References 77 publications

Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model

Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model

Lessons learned from cancer vaccine trials and target antigen choice

Tumor-Derived α-Fetoprotein Impairs the Differentiation and T Cell Stimulatory Activity of Human Dendritic Cells

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