Cancer immunity involves contrasting signals
activation suppression
Multiple immune cells interact with tumors but the key step is the activation of T cells
T cells
Tissue antigens
(MUC1, EPCAM, PSA, PSMA, PAP, Mart-1, CEA….…)
Embryonic antigens
(MAGE3, NY-ESO1, PRAME….)
Weak or no response
Self antigen
Strong response
Activation of T cells (IMMUNOGENICITY) is driven by tumor antigens
NEOANTIGENS
Neoantigen or foreign antigen Immune responses are based on
DNA “mutations”
•missense, frameshift, splice-site mutations
•insertion-deletion
•translocations
Sun exposure Smoking
Environmental factors
Genetic background HVB, HCV HPV
adenovirus EBV
Viral proteins expressed by tumor cell
T cell
Nature of cancer neoantigens
Non-silent DNA mutations Viral antigens
T cell
T cell
T cell receptor (TCR) CD8/CD4
Tumor neoantigen
HLA I/II Tumor
cell
Release of cytotoxic granules
(perforin, granzyme B) to kill the target cell Secretion of cytokines (IFN, TNF, others) to modulate the tumor microenvironment IFNg
T cell recognition of tumor antigens
triggers an event cascade
in tumor microenvironment
A A
Lymph node
Peripheral blood
Dendritic cells
A A
A A
Tumor-specific T cell activation
and clonal expansion
A A
Tumor cell apoptosis
T cell priming
Tumor neoantigens
T cell
homing to tumor site
Tumor killing
Cancer IMMUNOGENICITY induces tumor immunity by autovaccination
Effector
phase
A A
Lymph node
Peripheral blood
Dendritic cells
A A
A A
Tumor-specific T cell activation
and clonal expansion
A A
Tumor cell apoptosis
T cell priming
T cell
homing to tumor site
Tumor killing
Cancer IMMUNOGENICITY induces T cell exhaustion
Chronic immunostimulation
T cell exhaustion
Local accumulation of IFN and proinflammatory cytokines
Negative feedback mechanisms
Tumor neoantigens
CD28
CTLA-4 PD-1
TCR
PI-3K Grb-2
antigen HLA
PD-L1
T cell activation (IFNg) causes the expression of immune checkpoints
IFNg
CTLA-4
Acting in the PRIMINGphase by blocking T cell activation via dendritic cells and
potentiating the function of CTLA-4+ regulatory T cells (Treg)
Acting in the EFFECTOR phase by blocking T cell anti-tumor function (lysis, proliferation, cytokine release)
PD-L1 PD-1
Major activity on CD4+ memory T cells Major activity on CD8+ effector T cells
Multiple immune checkpoints block T cell function
Immune checkpoints are upregulated in tumor infiltrating T cells
Tumeh et al., Nature 2014
PD-1
Gentles et al., OncoImmunol 2015
Ki67
PD-1 TIM-3 CTLA-4
Highfill SL t al., Sci Transl Med. 2014
PD-L1 in tumor cells PD-L1 in tumor
infiltrating cells (myeloid cells)
Taube et al., Clin Cancer Res 2014 Oncogenic pathways
• HIF1a-hypoxia
• VHL
• EGFR activation
• AP-1 signaling
• PTEN loss
• PI3K/AKT/mTOR
HOT TUMOR COLD TUMOR Tumor cells
T cells and other
anti-tumor immune cells
Immunosuppressive and inflammatory cells
Cancer IMMUNOGENICITY and T cell infiltrate
defines HOT and COLD tumors
Chronic stimulation is associated
with the accrual of immunosuppressive cells
Antigen clearance
Memory T cells
Activation of negative feedback pathways
to downsize responses and avoid normal tissue damage Immune
suppressive cells
Immune checkpoints
Regulatory
T cells Myeloid derived suppressor cells
CTLA4 PD1
Treg TAM
COLD TUMORS produce factors attracting
immunosuppressive cells in tumor microenvironment
Promoting EMT and metastatization
-Myeloid-derived
suppressor cells (MDSC) -Tumor infiltrating
macrophages (TAM) - Regulatory T cells (Treg)
Immunosuppression Angiogenesis
Epithelial-to-
mesenchymal transition
HIF1a-hypoxia VHL
EGFR activation AP-1 signaling PTEN loss
PI3K/AKT/mTOR CCL2
GM-CSF
Low expression of neoantigens
Thorsson et al., Immunity 2018
Bad prognosis
Good prognosis
Macrophages Monocytes Granylocytes
Gentles et al., Nature med 2015
T cells
Tumor myelo- conditioning
factors
Monocytes Myeloid precursors
Treg
Spleen Lymph nodes Bone marrow
CD3+ T cells
Tumor lesion
Blood Altered monocytes
Myeloid-derived suppressor cells
Myeloid cells
inhibit T cell proliferation and function
Systemic immunosuppression is source of
predictive/prognostic biomarkers
Tumor myelo- conditioning
factors
Monocytes Myeloid precursors
Treg
Spleen Lymph nodes Bone marrow
CD3+ T cells
Cancer patients
Blood levels
Predictive and prognostic biomarkers
Tumor lesion
Blood Altered monocytes
Myeloid-derived suppressor cells
Myeloid cells
inhibit T cell proliferation and function
Systemic immunosuppression is source of
predictive/prognostic biomarkers
Vetsika et al., J Immunol Res 2014
Myeloid-derived suppressor cells accumulate in tumor and blood
of cancer patients in association with bad prognosis
Myeloid Index Score
Rivoltini et al., manuscript in prep Sade-Feldman et al., Clin Cancer Res 2016
Monocytic MDCS
Time
Probability
0 3 6 9 12 15 18 21 24 27 30
0.00.20.40.60.81.0
27 27 27 26 24 21 17 14 12 11 11 iBRAF
38 38 38 37 31 27 23 19 15 11 10 Ipi/Nivo
18 18 13 5 2 1 1 1 1 1 1 iBRAF
38 26 14 11 8 6 3 1 1 Ipi/Nivo
iBRAF Ipi/Nivo
iBRAF Ipi/Nivo
No. patients at risk
Index=0 Index>0
pvalue Therapy= 0.98 OS INDEX X THERAPY
Neutrophil to lymphocyte ratio
Ferrucci et al., Ann Oncol 2015
Anti-CTLA4 in melanoma
Anti-PD-1 in NSCLC
Diem et al., Lung Cancer 2017
Circulating myleoid cells as marker of
poor prognosis and resistance to therapy
HOT TUMOR
Exhausted T cells
Immune checkpoint inhibitors
PD-1/PD-L1 blockade Hyperexhausted T cells + Lag3 blockade
+ TIM3 blockade
Therapeutic approaches
in HOT tumors
HOT TUMOR
Exhausted T cells
Immune checkpoint inhibitors
PD-1/PD-L1 blockade Hyperexhausted T cells + Lag3 blockade
+ TIM3 blockade
Escaping tumor
HLA loss, Ag loss, APC loss
Local inflammatory stimuli (radiotherapy, chemotherapy, intratumor immonomodulation) Non-T cell immunity stimulation
Therapeutic approaches
in HOT tumors
Reduce/modify immunosuppression
•Chemotherapy (myelo-conditioning)
•Radiotherapy (TAM2->TAM1 conversion)
•Anti-angiogenics
•Novel “target” therapies (CSFR1, Arg1…)
How to turn cold
into hot tumors
Reduce/modify immunosuppression
•Chemotherapy (myelo-conditioning)
•Radiotherapy (TAM2->TAM1 conversion)
•Anti-angiogenics
•Novel “target” therapies (CSFR1, Arg1…)
Attract T cells
Local inflammatory stimuli
(radiotherapy, chemotherapy, immunomodulators) Adoptive immunotherapy (CART cells)
Cancer vaccines
