Active STAT5 promotes long lived cytotoxic CD8 T cells that induce regression of autochthonous mouse melanoma.
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1 Active STAT5 promotes long lived cytotoxic CD8 T cells that induce regression of autochthonous mouse melanoma. SITC 211 Grégory Verdeil No relationships to disclose
2 T cell adoptive transfer for cancer immunotherapy Short lived CD8 T cells, poor tissue infiltration High doses of IL 2 = systemic action of IL 2 (side effects) Reinfuse post-lymphodepletion High dose IL-2
3 Activation of IL2/STAT5 sustains CD8 T cells effector functions APC pmhc agonist TCR CD3 2 c 1 CD8 T cells JAK1 JAK3 NF B P STAT5 AP-1 STAT5 P GAS TATA Pol II Sustained expression of genes implicated in survival and cytolysis Verdeil et al. Journal of Immunology 26
4 Use of STAT5CA to increase tumor elimination by CD8 T cells Retroviral transduction of TCR transgenic CD8 T cells APC Expansion / differentiation Naïve TCR transgenic CD8 T cell (TCRP1A) Cytotoxic CD8 T cells
5 Preferential expansion and Safety tissue homing of STAT5CA T cells Day 21 in Immunocompetent hosts WT B1D2 (immunocompetent) LN Host cells 3.1 TCRP1A STAT5CA Lymphoid organs Day Day Spleen GFP 1 2 Day Lung STAT5CA GFP Liver Non lymphoid organs CD GFP
6 STAT5CA expressing T cells are maintained at a quiescent G state 1 Rag-/- (immunodeficient) % of CD8 GFP+ among PBLs Days Days after transfer in Rag 1 / hosts d3 d3 d14 Days after transfer in Rag 1 / hosts control TCRP1A effector STAT5CA TCRP1A effector STAT5CA TCRP1A effctor BrdU 7AAD S G/G1 G2/M BrdU injected ip 24h before analysis
7 Inducible melanoma model (TIRP mice) WT(immunocompetent) P1A+ In melanocytes HRas G12V on P1A cancer germline Ag on Ink4a/Arf off 36% 143 days of latency Rag-/- (immunodeficient) P1A+ 72% 82 days of latency In melanocytes HRas G12V on P1A cancer germline Ag on Ink4a/Arf off Amela Aggressive The adaptive immune system controls tumor growth in TIRP mice. Huijbers et al. Cancer research 26; Soudja et al. Cancer research 21
8 Amela tumors are strongly immunosuppressive VEGF G CSF IL 1 IL 6 CD11b Gr1 Arginase 1+ Cox 2+ Myeloid Derived Suppressor Cells Immunosuppressive environment Expression of inhibitory receptors Loss of functionnal properties Endogenous CD8 T cells have an exhausted phenotype Inside the tumor Positive control Amela tumor
9 Use of STAT5CA to increase tumor elimination by CD8 T cells Retroviral transduction of CD8 T cells to express STAT5CA APC Expansion / differentiation Naïve TCR transgenic CD8 T cell (TCRP1A) P1A+ Cytotoxic CD8 T cells Rag-/- (immunodeficient) HRas G12V on P1A cancer germline Ag on Ink4a/Arf off
10 STAT5CA expressing T cells induce melanoma regression in Rag / TiRP mice 7 days post treatment Grange et al. Cancer research in press
11 STAT5CA T cells remain active in the melanoma immunosuppresive environment TCRP1A GFP 1x1 6 TCRP1A GFP 7x1 6 TCRP1A STAT5CA 1x1 6 CD8 TILs FSC A GzmB Grange et al. Cancer research in press
12 STAT5CA T cells are more efficient than IL 2 complexes to induce tumor regression Luc+ transplanted melanoma immunocompetent TILs analysis Transferred TCRP1A TCs Endogenous TCs TCRP1A etc + IL 2c TCRP1A etc TCRP1A etc STAT5CA Grange et al. Cancer research in press
13 Conclusions -STAT5CA transduced T cells show high cytolytic potential and capacity to migrate into tissues/tumors - STAT5CA transduced T cells remain dependent on the presence of the antigen for restimulation - STAT5CA transduced T cells induce strong regression of an autochthonous melanoma with high immunosuppressive properties - What are the mechanisms involved in resistance of STAT5CA transduced T cells to immunosuppression?
14 CIML Anne-Marie Schmitt-Verhulst s Lab Nathalie Auphan-Anezin Magali Grange Michel Buferne Marielle Mello Marilyn Giordano Annick Guimezanes Amandine Mas Claude Boyer Pierre Mouchacca Saïdi M homa Soudja Maria Wehbe
15 T cell adoptive transfer for cancer immunotherapy STAT5-CA? No need of IL 2 injections = Targeted action on CD8 Te Long lived CD8 Te (>d14) Tissue infiltration For safety: coupling to a suicide gene
16 Lymphoid organs Peripheral Tissues Naïve CD8 TC Antigen priming Early CD8 effector TC Full CD8 effector TC CD62L - CCR7 - IL-7Rα - IL-2Rα+ CD44+ IL-2Rβ+ GzmB hi KLRG1 ++ Tissue Homing Immediate functions Short-lived +Stat5 Lymphoïd organs Inducible functions High replicative potential CD62L + CCR7 + IL-7Rα + CD44 + IL-2Rβ + IL-2Rα _ GzmB lo KLRG-1 - Central memory CD8 TC Memory CD8 etc-stat5ca CD62L - CCR7 - IL-7Rα - CD44+ IL-2Rβ+ IL-2Rα + GzmB hi KLRG-1 - Effector Memory CD8 TC CD62L - CCR7 - IL-7Rα - CD44 + IL-2Rβ + IL-2Rα _ GzmB hi KLRG-1 + Tissue Homing Immediate functions Poor replicative potential Tissue Homing Immediate functions High replicative potential
17 STAT5CA TCRP1A CD8 T cells also reject a P1A+ melanoma in immunocompetent hosts STAT5CA expressing CD8 T cells show a higher expansion and tumor infiltration than non manipulated CD8 Te counterparts Recipients = LysoM egfp Ly5.1 B1.D2 D: 1 6 T429 luc retro peritoneal Day 21 Adoptive Transfer Day 24 Day 24+1 Day 24+7 Day 24+1 TCRP1A Te (1 6 cells) TCRP1A STAT5CA Te (1 6 cells) No Ph emission but small residual tumor analysis TCRP1A STAT5CA effectors Host CD8 TL GzmB TCRP1A effectors
18 Day LysoM egfp B1.D2 Adoptive therapy in mice bearing a transplanted melanoma TCRP1A etc STAT5CA i.v. Or TCRP1A etc Or TCRP1A etc + IL 2c (day+1;+2;+3;+5;+7;+9) Monitoring of tumor growth by bioluminescence TCRP1A etc TCRP1A etc + IL 2c TCRP1A etc STAT5CA Analysis day +11 post adoptive transfer TCRP1A etc STAT5CA TCRP1A etc TCRP1A etc + IL 2c TILs analysis Transferred TCs Endogenous TCs CRP1A CD8 etc STAT5CA nduce regression of a 1A + transplanted melanoma in immuno competent hosts TCRP1A CD8 etc STAT5CA show a higher intra tumor accumulation than non manipulated CD8 etc, even when coupled to IL 2c infusions.
19 Transfer of TCRP1A etc STAT5CA Transfer of TCRP1A etc Transfer of TCRP1A etc + IL 2c Compared to endogenous CD8 TILs, TCRP1A etc STAT5CA expressed higher levels of GzmB and responded efficiently to recall restimulation.
20 Current adoptive therapies use highly differentiated effector CD8 T cells ex vivo expansion T cell culture + IL 2 + Ag (From Rosenberg et al) High number of T cells with high doses of IL 2 = systemic action of IL 2/dise effects (including on Tregs) Short lived CD8 Te (up to d14) Poor tissue infiltration STAT5CA based adoptive therapies promote less-differentiated and long-lived effector CD8 T cells No further expansion T cell culture + STAT5CA Low number of T cells No need of IL 2 injections = Targeted action on CD8 Te Long lived CD8 Te (>d14) Tissue infiltration For safety: coupling to a suicide gene
21 <YOUR NAME HERE> The following relationships exist related to this presentation: <No Relationships to Disclose> <OR> <COMPANY X, Received, Role (i.e. BMS, Honorarium, Speaker)> <COMPANY Y, Received, Role (i.e. Pfizer, Salary, Employee)> 21
22 STAT5CA expressing CD8 T cells have a T effector memory phenotype CD CD CD127 1 TCRP1ASTAT5CA Te (d41) TCRP1A Te (d41) CD8 Tn Splenocytes CD44 GzmB CD62L CCR7 MOMA B22 GFP In correlation with CCR7 downmodulation, STAT5CA transduced T cells are found in the red pulp (d6 after transfer in B1D2 syngenic mice, spleen)
23 Inducible melanoma model (TiRP mice) Inducible melanoma P1A+ HRas G12V on P1A cancer germline Ag on Ink4a/Arf off TiRP mice Mela (pigmented) Amela (unpigmented) Incidence (Number/%) 29 (8. %) 94 (26. %) Mela Slow progressing Latency (days) Growth (mm 3 /day) Amela Aggressive Huijbers et al.26; Soudja et al. 21
24 Effector function +Ag peptide Day Day 3 Day 3 Day 7 +Ag peptide +Ag peptide Day 3 Day 7
25 Les tumeurs Amela sont associées à l inflammation Mela Amela TiRP -/- traitées au 4OH Sérum Multiplex ELISA Ratio comparé aux souris contrôles ns Mela Amela IL-1α IL-1βIL-2 IL-4 IL-5 IL-6 IL-1IL-12 IL-13 IL-17 FGF GM-CSF G-CSF VEGF KC MCP-1 MIP1γ MIG IP1 INFγ TNFα M homa Soudja S. Wehbe M. Mas A. 29
26 Les tumeurs Amela sont associées à l inflammation Mela Amela TiRP -/- traitées au 4OH Sérum Multiplex ELISA Ratio comparé aux souris contrôles ns Mela Amela IL-1α IL-1βIL-2 IL-4 IL-5 IL-6 IL-1IL-12 IL-13 IL-17 FGF GM-CSF G-CSF VEGF KC MCP-1 MIP1γ MIG IP1 INFγ TNFα Mobilisation M homa Soudja S. Wehbe M. Mas A. 29
27 Les tumeurs Amela sont associées à l inflammation Mela Amela TiRP -/- traitées au 4OH Sérum Multiplex ELISA Ratio comparé aux souris contrôles ns Mela Amela IL-1α IL-1βIL-2 IL-4 IL-5 IL-6 IL-1IL-12 IL-13 IL-17 FGF GM-CSF G-CSF VEGF KC MCP-1 MIP1γ MIG IP1 INFγ TNFα M homa Soudja S. Wehbe M. Mas A. 29 Recrutement
28 Les tumeurs Amela sont associées à l inflammation Mela Amela TiRP -/- traitées au 4OH Sérum Multiplex ELISA Ratio comparé aux souris contrôles ns Mela Amela IL-1α IL-1β IL-2 IL-4 IL-5 IL-6 IL-1 IL-12 IL-13 IL-17 FGFGM-CSF G-CSF VEGF KC MCP-1 MIP1γ MIG IP1 INFγ TNFα Polarisation de la réponse immunitaire (Th2/Th17) M homa Soudja S. Wehbe M. Mas A. 29
29 Grégory Verdeil Active STAT5 promotes long lived cytotoxic CD8 T cells that induce regression of autochthonous mouse melanoma. No relationships to disclose
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