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Escape from immune control can be viewed as one of the «Hallmarks of Cancer»
D. Hanahan and R. A. Weinberg, Cell, 2011
D. Hanahan , R. A. Weinberg, Cell, 2011
Cancer stroma comprises different immune cells
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
W. H. Fridman et al., Nat. Rev. Cancer, 2012 Courtesy of Jerome Galon
20 cancer types analyzed
A. J. Gentles et al., Nat. Med., 2015
Computational meta-analysis of expression signatures from 18,000 human tumors reveals positive and negative correlations between tumor-infiltrating leukocytes and patient survival
Myeloid cells of innate immunity
Dendritic cells
Mast cells
Neutrophils
Monocytes/Macrophages
Phagocytosis, inflammation, antimicrobial peptide production
Phagocytosis, inflammation, tissue repair
Eosinophils
Inflammation, vascular permeability
Defense against parasites
Activation of naïve T cells
Cell type Main function in immune response
M. G. Manz and S. Boettcher, Nat. Rev. Immunol., 2014
Steady-state hematopoyesis
Monocyte and macrophage developmental pathways (before birth and under steady-state condition)
F. Ginhoux and S. Jung, Nat Rev Immunol., 2014
Classic and alternative activation of macrophages
K. Abbas K, A. H. Lichtman. Cellular and Molecular Immunology, 7th Edition
Macrophage plasticity
J. P. Murray et al., Immunity, 2014
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
M. G. Manz and S. Boettcher, Nat. Rev. Immunol., 2014
Emergency granulopoiesis
c/EBP
V. Bronte et al., Nat. Comm., 2016
E. Timosenko et al., Immunotherapy, 2016
The metabolic control of T cell activation by myeloid cells
P. J. Murray, Nat. Immunol., 2016
Amino acid metabolizing enzymes with immuno regulatory activity
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 H2O2 and
phenylpyruvate
IL-4/IL-13 DC, B lymphocytes
Amino acid metabolizing enzymes and control of immune response
D. H. Munn and A. L. Mellor, Trends Immunol., 2016
WTNosKOArgNosKO
E 7 s.c. injectionG
Day 0 Day 7 Day 50
0.5x10 OT-1 CTL or PBS i.v. injection
6
Tumor reached 2000 mm3
A
Mouse sacrifice
ARG1 genetic ablation favors immunotherapy
I. Marigo et al., Cancer Cell, 2016
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
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
An exemplified comparison of macrophage and DC ontology
M. Guilliams et al., Nat. Rev. Immunol., 2014
L. Corrales et al., Cell Research, 2017
Tumor-infiltrating DCs can activate CD8+ T cells
S. Spranger et al., Nature, 2015 S. Spranger and T. Gajewsky, Adv. Immunol., 2016 S. Spranger and T. Gajewsky, Oncoimmunology, 2015
Oncogenic landscape influences T cell infiltration (-catenin in melanoma)
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
Intratumoral transfer of Nos2+ TipDCs is required for tumor rejection following ACT
I. Marigo et al., Cancer Cell, 2016
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
V. Bronte and P. J. Murray. Nat. Med. 2015
Therapeutic interventions to improve cancer therapy
W. Zheng and J. W. Pollard, Cell Research, 2016 M. M. Kaneda et al., Nature, 2016 O. De Henau et al., Nature, 2016
Targeting PI3K in myeloid cells
gal CTLs
Ablation + mTERT CTLs
No Ablation + mTERT CTLs
C57BL/6 c/ebp; Tie2Cre
flox/+ c/ebp;
Tie2Cre
flox/flox
0
20
60
40
80
100
0 20 40 60 0 20 40 60 0 20 40 60
% s u
r v i v
a l
Days after adoptive transfer
+/+ +/- -/-
P<0.01
I. Marigo et al., Immunity, 2010
Targeting cEBP in myeloid cells
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
Reprogramming the bone marrow by enforced miR-142-3p expression
N. Sonda et al., 2013, Immunity
Days
Ly6C+ Monocytes
M2 macrophages PMN-MDSCs
DCs M1 macrophages
Cancer
?
N. Sonda et al., 2013, Immunity
Reprogramming the bone marrow by enforced miR-142-3p expression
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.
Chemotherapy Radiotherapy
CD11b CSF1R CCL2
cEBP Gata6 PI3K miR-142-3p
Refining therapeutic strategies to alter myeloid compartment in cancer
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