Manipulating the Tumor Environment

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1 Manipulating the Tumor Environment Vincenzo Bronte Verona University Hospital

2 Escape from immune control can be viewed as one of the «Hallmarks of Cancer» D. Hanahan and R. A. Weinberg, Cell, 2011

3 Cancer stroma comprises different immune cells D. Hanahan, R. A. Weinberg, Cell, 2011

4 Meta-analysis of 124 published articles studying the impact of cytotoxic T cells, memory T cells, and T-helper subpopulations with regards to prognosis of patients with cancer 20 cancer types analyzed W. H. Fridman et al., Nat. Rev. Cancer, 2012 Courtesy of Jerome Galon

5 Computational meta-analysis of expression signatures from 18,000 human tumors reveals positive and negative correlations between tumor-infiltrating leukocytes and patient survival A. J. Gentles et al., Nat. Med., 2015

6 Myeloid cells of innate immunity Cell type Main function in immune response Monocytes/Macrophages Neutrophils Dendritic cells Phagocytosis, inflammation, tissue repair Phagocytosis, inflammation, antimicrobial peptide production Activation of naïve T cells Mast cells Inflammation, vascular permeability Eosinophils Defense against parasites

7 Steady-state hematopoyesis M. G. Manz and S. Boettcher, Nat. Rev. Immunol., 2014

8 Monocyte and macrophage developmental pathways (before birth and under steady-state condition) F. Ginhoux and S. Jung, Nat Rev Immunol., 2014

9 Classic and alternative activation of macrophages K. Abbas K, A. H. Lichtman. Cellular and Molecular Immunology, 7th Edition

10 Macrophage plasticity J. P. Murray et al., Immunity, 2014

11 Metabolic and molecular pathways for TAM programming Notch-Rbpj VEGF TGF O. R. Colegio et al., Nature, 2014 V. Bronte, Immunology and Cell Biology, 2014

12 Emergency granulopoiesis c/ebp M. G. Manz and S. Boettcher, Nat. Rev. Immunol., 2014

13

14 V. Bronte et al., Nat. Comm., 2016

15 The metabolic control of T cell activation by myeloid cells E. Timosenko et al., Immunotherapy, 2016

16 Amino acid metabolizing enzymes with immuno regulatory activity P. J. Murray, Nat. Immunol., 2016

17 Amino acid metabolizing enzymes and control of immune response Enzyme Substrate Effects of enzymatic activity Main cytokine controlling expression Cell type Indoleamine 2,3- dioxygenase L-tryptophan L-tryptophan depletion and kinurenine IFN- Plasmacitoid DC, MØ, DC subsets, some tumors Arginase L-arginine L-arginine depletion, urea and polyamines IL-4/IL-13 MDSC, MØ, some tumors Nitric Oxide Synthase L-arginine NO IFN- MDSC, MØ Interleukin-4- induced gene 1 (oxidase) L-phenylalanine H 2 O 2 and phenylpyruvate IL-4/IL-13 DC, B lymphocytes

18 D. H. Munn and A. L. Mellor, Trends Immunol., 2016

19 ARG1 genetic ablation favors immunotherapy A WT NosKO ArgNosKO EG7 s.c. injection 6 0.5x10 OT-1 CTL or PBS i.v. injection Tumor reached 2000 mm3 Day 0 Day 7 Day 50 Mouse sacrifice I. Marigo et al., Cancer Cell, 2016

20 Current clinical trials Indoleamine 2 3-dioxygenase 1 (IDO1) - About 24 clinical trials in cancers (mostly in combination with checkpoint inhibitors or other cancer therapies) - 4 small molecule inhibitors and one vaccine Arginase 1 (ARG1) - 3 clinical trials, only one in cancer - Small molecule inhibitor Ornithine decarboxylase (ODC) - About 34 clinical trials (Trypanosoma infections, cancer prevention and treatment, alone or in combination) - Small molecule inhibitor

21 Dendritic cells (DCs) in cancer immunity Many tumors have few or immature DCs Conventional (c)dcs of are necessary for inducing and maintain T-cell responses to cancer cdc1 type depend of BATF3 transcription factor and have enhanced ability to cross-present antigens Among cdc1, migratory CD103 + DCs in mice are capable of capturing tumor antigens and present them to CD8 + T cells in lymph nodes and within the tumor environment Sensing of damage-associated molecular pattern (DAMP) signals by receptor of innate immunity triggers release of type I interferon and fuel CD8 + T cell priming (example: STING, immunogenic cell death) Tumor-specific CD8 + T cells can stimulate inflammatory DCs derived from monocytes to help the destruction of cancer cells

22 An exemplified comparison of macrophage and DC ontology M. Guilliams et al., Nat. Rev. Immunol., 2014

23 Tumor-infiltrating DCs can activate CD8 + T cells L. Corrales et al., Cell Research, 2017

24 Oncogenic landscape influences T cell infiltration ( -catenin in melanoma) S. Spranger et al., Nature, 2015 S. Spranger and T. Gajewsky, Adv. Immunol., 2016 S. Spranger and T. Gajewsky, Oncoimmunology, 2015

25 Tumor-specific CD8 + T cells collaborate with Tip-DCs I. Marigo et al., Cancer Cell, 2016 S. Pilon-Thomas and B. Ruffell, Cancer Cell, 2016

26 Intratumoral transfer of Nos2 + TipDCs is required for tumor rejection following ACT I. Marigo et al., Cancer Cell, 2016

27 Cold and immune-evasive tumors: the micro-environment as target Cancer cell molecular programs -catenin Signaling and transcription factors in myeloid infiltrating cells PI3K, c/ebp, mir142-3p Chemochines, cytokines and chemoattractants CCL2, CCL3, CCL4, CSF-1 Enzymes IDO1, Arginase 1 Myeloid cell activation and biology Anti-CD47, TLR4 agonists, STING agonists, TLR9 agonists

28 Therapeutic interventions to improve cancer therapy V. Bronte and P. J. Murray. Nat. Med. 2015

29 Targeting PI3K in myeloid cells W. Zheng and J. W. Pollard, Cell Research, 2016 M. M. Kaneda et al., Nature, 2016 O. De Henau et al., Nature, 2016

30 Targeting cebp in myeloid cells % s u r v i v a l C57BL/6 flox/+ c/ebp; Tie2Cre flox/flox c/ebp; Tie2Cre +/+ +/- -/ Days after adoptive transfer P<0.01 gal CTLs No Ablation + mtert CTLs Ablation + mtert CTLs I. Marigo et al., Immunity, 2010

31 Among mirs down-regulated in tumor-infiltrating myeloid cells, mir-142-3p promotes the macrophage differentiation by controlling cebp N. Sonda et al., 2013, Immunity

32 Reprogramming the bone marrow by enforced mir-142-3p expression N. Sonda et al., 2013, Immunity

33 Reprogramming the bone marrow by enforced mir-142-3p expression Days Ly6C + Monocytes? M1 macrophages DCs M2 macrophages PMN-MDSCs Cancer N. Sonda et al., 2013, Immunity

34 Conclusions Targeting myeloid cells is likely not going to be effective as single therapy but can enhance cancer immunotherapy. Single or combinatorial approaches depleting macrophages for prolonged times might have secondary effects on tissues homeostasis. Treatments that acts on cell plasticity might offer some advantages over simple depletion. Intratumoral DC activation can promote a sustained T cell response. Further characterization of tumor-infiltrating myeloid cells might provide better molecular targets for intervention.

35 Refining therapeutic strategies to alter myeloid compartment in cancer Chemotherapy Radiotherapy CD11b CSF1R CCL2 cebp Gata6 PI3K mir-142-3p

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