Restoring Immune Function of Tumor-Specific CD4 + T Cells during Recurrence of Melanoma
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1 Restoring Immune Function of Tumor-Specific CD4 + T Cells during Recurrence of Melanoma Goding SR et al. J Immunol 2013; 190: C. Nikolowsky Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration Medical University Vienna
2 Background Melanoma Stages and Therapy Adoptive T Cell Transfer Reccurence Tregs PD-1 LAG-3 TIGIT TIM-3
3 Melanoma Surgery with or without lymph node sampling Chemotherapy (CHT) systemic or regional Biologic therapy IFN, IL-2, TNF Targeted therapy mabs, Signal transduction inhibitors, Oncolytic viruses, Angiogenesis inhibitors Radiation therapy
4 Melanoma Stage 0 (melanoma in situ) Surgery Stage I & II (invasive melanoma) Surgery + lymph node sampling Stage III (regional metastasis) Surgery + biologic therapy Targeted therapy + regional CHT (+ biologic therapy) Stage IV (distant metastasis) and Reccurent Melanoma Targeted therapy Biologic therapy CHT Palliative therapy (Surgery, Radiotherapy)
5 Tumor-Specific T cells Adoptive Cell Transfer (ACT) Tumor-infiltrating Lymphocytes (TIL) genetically engineered T cells In vitro reproduction Lymphodepletion Re-Infusion Jennifer Makalowski and Hinrich Abken (2013). Adoptive Cell Therapy of Melanoma: The Challenges of Targeting the Beating Heart, Melanoma - From Early Detection to Treatment, Dr. Ht Duc (Ed.), ISBN: , InTech, DOI: /53619.
6 Adoptive Cell Transfer Jennifer Makalowski and Hinrich Abken (2013). Adoptive Cell Therapy of Melanoma: The Challenges of Targeting the Beating Heart, Melanoma - From Early Detection to Treatment, Dr. Ht Duc (Ed.), ISBN: , InTech, DOI: /53619.
7 Adoptive Cell Transfer (ACT) Effective as primary treatment under regulatory T cell (Treg) depletion Less effective for treatment of recurring melanoma effector T cell (T E ) inhibiting molecules Programmed cell death protein 1 (PD-1) Lymphocyte-activation gene 3 (LAG-3) T cell immunoreceptor with Ig and ITIM domains (TIGIT) T cell immunoglobulin mucin-3 (TIM-3)
8 Materials and Methods Mice Tyrp1 B-w RAG -/- TRP-1-specific CD4 + TCR transgenic mice were crossed with Foxp3-DTR mice to create tyrp1 B-w RAG -/- Foxp3-DTR TRP-1-specific CD4 + TCR transgenic mice no CD8+ T cells T cell receptor is TRP-1 specific Tregs can be inactivated with DT C57BL/6 RAG -/- mice
9 Tumor Line Materials and Methods B16.F10 (H-2 b ): TRP-1 + spontaneous murine melanoma injected s.c. at 2x10 5 cells/mouse
10 Tumor-specific Foxp3 + Tregs expand during recurrence CD57BL/6 mice ACT 10 days after tumor inoculation Recurrence variable (30 to 120 d)
11 Tumor-specific Foxp3+ Tregs expand during recurrence higher levels of Tregs in mice with relapse
12 Tumor-specific Foxp3+ Tregs expand during recurrence higher levels of Tregs in mice with relapse T E approximately the same
13 Depletion of tumor-specific Foxp3 + T cells does not treat recurrence
14 Depletion of tumorspecific Foxp3+ T cells does not treat recurrence It also doesn t prevent it
15 Depletion of tumor-specific Foxp3+ T cells does not treat recurrence Differences in IFN and TNF production suggest intrinsic dysfunction of CD4 + T E
16 Tumor-specific CD4+ T cells become exhausted during cancer recurrence
17 Tumor-specific CD4+ T cells become exhausted during cancer recurrence
18 Tumor-specific CD4+ T cells become exhausted during cancer recurrence
19 Tumor-specific CD4+ T cells become exhausted during cancer recurrence
20 PD-L1-specific blockade restores antitumor immunity and treats recurrence only in combination with tumor-specific Treg ablation
21 PD-L1-specific blockade restores antitumor immunity and treats recurrence only in combination with tumor-specific Treg ablation
22 PD-L1-specific blockade restores antitumor immunity and treats recurrence only in combination with tumor-specific Treg ablation
23 PD-L1-specific blockade restores antitumor immunity and treats recurrence only in combination with tumor-specific Treg ablation
24 Disparate treatment requirements between primary and recurrent cancer
25 Simultaneous blockade of PD-L1 and LAG-3 in vivo treats recurring tumors, overcoming the necessity to deplete tumor-specific Tregs
26 Simultaneous blockade of PD-L1 and LAG-3 in vivo treats recurring tumors, overcoming the necessity to deplete tumor-specific Tregs
27 Simultaneous blockade of PD-L1 and LAG-3 in vivo treats recurring tumors, overcoming the necessity to deplete tumor-specific Tregs
28 Discussion Treg-mediated suppression and chronic exhaustion of CD4 + T cells are are intertwined during melanoma recurrence. Suppression of antitumor immunity is not Treg dependent Anti-LAG-3 mabs have the same effect as Treg depletion Impact of endogenous Tregs, B cells and CD8+ T cells?
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