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CATALYST: The Immuno‐oncology Revolution Continues: A 3D ViewChapter 2: Mechanisms of Immune Escape
Jason Luke, MD, FACPAssistant Professor of Medicine
The University of ChicagoMedicine & Biological Sciences
Chicago, IL
Disclosures• Consultancy:
– 7 Hills, Actym, Amgen, Array, AstraZeneca, BeneVir, Bristol‐Myers Squibb, Castle, CheckMate, EMD Serono, Gilead, Janssen, Merck, NewLink, Nimbus, Novartis, Palleon, Syndax, Tempest, WntRx
• Research Support to Institution:– AbbVie, Array, Boston Biomedical, Bristol‐Myers Squibb, Celldex, CheckMate, Corvus, Delcath, Five Prime, Genentech, Immunocore, Incyte, Intensity, MedImmune, Macrogenics, Novartis, Palleon, Pharmacyclics, Merck, Tesaro
This activity is supported by an educational grant from Bristol‐Myers Squibb.
Learning Objectives
• Discuss the pathophysiology of adult malignancies with a focus on tumor immunosurveillance and immune evasion
• Describe immune pathways that may be targeted to overcome immune‐evasion mechanisms and emerging clinical data on novel immuno‐oncology agents
• Review significant advances and unmet medical needs associated with currently available immuno‐oncology therapies including innate and adaptive resistance mechanisms (e.g., T‐cell exhaustion)
The Cancer Immunogram
LDH = Lactate dehydrogenase; CRP = C‐reactive protein. Blank CU et al. Science. 2016;352:658‐660. Pitt JM et al. Immunity. 2016;44:1255‐1269.
Tumor sensitivityto immune effectorsMHC expression,IFN‐γ sensitivity
General immune statusLymphocyte count
Tumor foreignnessMutational load
Immune cell infiltrationIntratumoral
T cells
Absence of checkpointsPD‐L1
Absence of soluble inhibitorsIL‐6, CRP
Absence of inhibitory tumor metabolism
LDH, glucose utilization
• Cancers cells express neo‐antigens; often recognized by the immune system
• Immune evasion mechanisms are prominent in tumors in which a host immune response has been generated
• Can be cancer‐cell intrinsic or extrinsic• Intrinsic immune evasion mechanisms:
• Loss or down‐regulated antigen‐presentation machinery
• PD‐L1 upregulation• Poor T cell co‐stimulation• Loss of class I molecules
• Extrinsic immune evasion mechanisms:• Recruitment of immune suppressive
cell populations (TAM, MDSC, Tregs)• Inhibitory enzymes (IDO, arginase)
and cytokines (IL‐10, TGF‐b)
Tumors Activate Immune Escape Mechanisms
IDO = Indoleamine 2,3‐dioxygenase; TAM = tumor‐associated macrophage; MDSC = myeloid‐derived suppressor cell.
Please put on your 3D glasses
Mechanisms of Immune Escape3D Video
The Tumor Immunity Continuum
Hegde PS et al. Clin Cancer Res. 2016;22:1865‐1874.
Inflamed Non‐inflamed
Preexisting immunity Immunologically ignorantExcluded infiltrate
Mutational load
Respond favorably tocheckpoint inhibition
Convert to inflamed phenotype with combinations
AngiogenesisReactive stroma
MDSCsProliferating
tumorsLow MHCclass I
TILsCB8 T cells/IFNγ
PD‐L1/checkpoints
MDSC = myeloid‐derived suppressor cell; MHC = Major histocompatibility complex.
Noninflamed Tumor Phenotype
• Poor effector cell trafficking due to:
• High expression of vascular markers, macrophages, fibroblasts
• Low inflammation and chemokineexpression, few lymphocytes
Gajewski, et al. Curr Opin Immunol. 2011;23:286‐292.
Inflamed Tumor Phenotype
• T cell recruitment • High levels of innate immune signals
• Chemokine expression
• Nevertheless, negative immune regulators dominate
CytotoxicT cell
Gajewski, et al. Curr Opin Immunol. 2011;23:286‐292.
Eliciting Anti‐Tumor Immunity in “T Cell‐Inflamed” vs “Non‐Inflamed” Cancers
Sharma P, et al. Science. 2015;348:56‐61.
Cancer Immunity: A Balancing Act
Immune Escape:• Antigen Presentation
• Loss of antigen (immune‐editing), • HLA
• Immune Checkpoints• PD1/PD‐L1• CTLA4• TIM3 and others
• Cytokines: TGF‐β, IL‐4, IL‐6• Immunosuppressive
microenvironment: IDO• Cellular Immune Escape
• T‐regs, M2 macrophages, MDSCs; T‐cell anergy
Immune Surveillance:• Immune system recognizes
malignant cells
IDO = Indoleamine 2,3‐dioxygenase; HLA = human leukocyte antigens; PD‐L1 = Programmed death ligand; CTLA4 = cytotoxic T‐lymphocyte protein 4; TIM3 = T‐cell immunoglobulin and mucin‐domain containing‐3
Stratification Based on Microenvironment
O’Donnell JS et al. Nat Rev Clin Oncol. 2019;16;151‐67.
PD-L1 upregulation is driven by IFN- from T cells infiltrating solid tumors
Daud A et al. ASCO 2015; 2. Garon EB et al. ESMO 2014; 3. Seiwert T et al. ASCO 2015; 4. Plimack E et al. ASCO 2015; 5. Nanda R et al. SABCS 2014; 6. Bang YJ et al. ASCO 2015 ; 7. Moskowitz C et al. ASH 2014; 8. Zinzani PL et al. ASH 2015; 9. Alley EA et al. AACR 2015; 10. Varga A et al. ASCO 2015; 11. Ott PA et al. 2015 ASCO; 12. Doi T et al. ASCO 2015; 13. Hsu C et al. ECC 2015; 14. Ott PA et al. ECC 2015; 15. Bang Y‐J et al. ECC 2015; 16. O’Neil B et al. ECC 2015; 17. Rugo HS et al. SABCS 2015;18. Frenel JS et al. ASCO 2016; 19. Mehnert JM et al. ASCO 2016; 20. Cohen R et al. ASCO
PD‐1/PD‐L1 Pathway: A Dominant Immune Escape Pathway in Human Cancer
TCR = T‐cell receptor; MHC = major histocompatibility complex; STAT = Signal transducer and activator of transcription.
Inhibition of T lymphocytes
Normal Function of Immune Checkpoints: CTLA4, PD1, and PD‐L1
Sharma P et al. Nat Rev Cancer. 2011;11:805‐812.
T cell T cellAPC APCAntigenTCR
TCRAntigen
CD‐28
CD‐28
B7
Activation of T lymphocytes
CTLA = cytotoxic T‐lymphocyte antigen; PD‐L = PD ligand; TCR = T‐cell receptor; MHC = major histocompatibility complex.
PD‐1
PD‐L1
Immune Checkpoint Inhibitors Mechanism of Action
Proliferation
Cytokines(IFN‐g)Cytotoxicity
Exhausted T cellImmune response
APCTumor cell
Proliferation
Cytokines(IFN‐g)Cytotoxicity
Reinvigorated T cellImmune response
APCTumor cell
PD‐1
PD‐L1
TCR
MHC
Immune Checkpoint InhibitorsMechanism of Action (continued)
Summary
• Immunotherapy response is impacted by factors related to the tumor, the host/patient, and the microenvironment
• Mechanisms of immune escape/resistance can be stratified by the T‐cell inflamed and non‐T‐cell inflamed tumor microenvironment
• Immune checkpoint inhibitors generally take advantage of pre‐existing immune response in the context of T‐cell inflammation
UP NEXT: CHAPTER 3
CATALYST: The Immuno‐oncology Revolution Continues: A 3D View
Chapter 3: Resistance or Non‐Response to Treatment
Mario Sznol, MDProfessor of Medicine (Medical Oncology)
Co‐Director, Cancer Immunology Program at Yale Cancer CenterCo‐Director, Yale SPORE in Skin Cancer
New Haven, CT