Immuno-oncology

Oral

Immune Checkpoint Blockade Recovers the Functionality of Tumor-infiltrating T Cells in Hepatocellular Carcinoma

Wednesday, June 14
6:15 PM - 7:45 PM

Targeting immune checkpoint co-inhibitory pathways is a promising novel therapeutic approach for several types of cancer. Therefore, we aimed to determine which co-inhibitory pathways can be targeted to enhance the functionality of intra-tumoral T cells in hepatocellular carcinoma (HCC).


We measured the expression of co-inhibitory receptors and ligands on leukocytes isolated from paired tumors, tumor-free liver tissues (TFL), and peripheral blood of HCC patients, and studied the effects of blocking co-inhibitory pathways on functional responses of CD4+ and CD8+ tumor-infiltrating lymphocytes (TIL) in ex vivo assays.


Expression of PD-1, TIM-3, LAG-3 and CTLA-4 on CD8+ T cells and/or CD4+Foxp3- T helper cells was significantly higher in tumors than in TFL or blood. Dendritic cells, monocytes and B cells in tumors expressed their ligands. Using MHC class I multimers loaded with immunogenic Glypican-3 or MAGE-C2 peptides, we found that PD-1, TIM-3 and LAG-3 expressions were selectively increased on tumor-associated antigen-specific CD8+ TIL. Compared to the TIL without co-inhibitory receptor expression, CD8+ and CD4+ TIL expressing those co-inhibitory receptors displayed a more activated status but similar or decreased granzyme B expression and effector cytokine production. Blocking PD-L1, TIM-3 or LAG-3 with neutralizing antibodies enhanced proliferative and cytokine responses of CD8+ and CD4+ TIL to polyclonal CD3/D28-stimulation as well as to Glypican-3 or MAGE-C2 presented by mRNA-transfected autologous antigen-presenting cells. Importantly, combining PD-L1 blockade with TIM-3, LAG-3 or CTLA-4 blockade further enhanced ex vivo TIL responses.


Conclusions: PD-1, TIM-3 and LAG-3 may be promising immunotherapeutic targets for the most prevalent primary liver cancer.

Guoying Zhou

Eramus MC - University Medical Centre

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    Dave Sprengers

    Erasmus MC-University Medical Center

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      Patrick Boor

      Erasmus MC-University Medical Center

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        Michail Doukas

        Erasmus MC-University Medical Center

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          Hannah Schutz

          Erasmus MC-University Medical Center

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            Shanta Mancham

            Erasmus MC-University Medical Center

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              Wojciech Polak

              Erasmus MC-University Medical Center

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                Jeroen de Jonge

                Erasmus MC-University Medical Center

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                  Marcia Gaspersz

                  Erasmus MC-University Medical Center

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                    Alexander Pedroza-Gonzalez

                    Erasmus MC-University Medical Center

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                      Haidong Dong

                      Mayo Clinic College of Medicine

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                        Kris Thielemans

                        Vrije Universiteit

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                          Qiuwei Pan

                          Erasmus MC-University Medical Center

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                            Jan IJzermans

                            Erasmus MC-University Medical Center

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                              Marco Bruno

                              Erasmus MC-University Medical Center

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                                Jaap Kwekkeboom

                                Erasmus MC- niversity Medical Center

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                                  Immune Checkpoint Blockade Recovers the Functionality of Tumor-infiltrating T Cells in Hepatocellular Carcinoma



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