Download Tumor Antigen Presentation to T Cells

The Science Behind
Immuno-Oncology
©2015 Bristol-Myers Squibb Company. ONCNL15NP04407-10 07/15
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Immuno-Oncology: Overview
Immune-Tumor Interactions
2
Key Points/Learning Objectives
• 
The immune system is complex,
made up of multiple mechanisms
that act to defend and protect the
human body1,2
–  Both innate and adaptive mechanisms are
involved1,3-5
• 
• 
The immune system can destroy
tumor cells via several mechanisms,
including T-cell−dependent targeting6
Cancer can evolve to evade
immune-mediated clearance through
a variety of mechanisms6,7
1.  Janeway CA, et al. Immunobiology: The Immune System in Health
and Disease. 6th ed. New York, NY: Garland Science; 2004.
2.  Pardoll DM. Nat Rev Cancer. 2012;11:252-264.
3.  Padmanabhan RR, et al. J Leuk Biol. 1988;43:509-519.
4.  Kim R, et al. Immunology. 2007;121:1-14.
5.  Vivier E, et al. Science. 2011;331:44-49.
6.  Kirkwood JM, et al. CA Cancer J Clin. 2012;62:309-335.
7.  Drake CG, et al. Adv Immunol. 2006;90:51-81.
3
Adaptive and Innate Immune Responses1-4
•  The adaptive response,
capable of responding to new
antigens (for example, T-cell or
B-cell activation via antigen
presentation)
•  The innate response,
involving proteins and cells
(for example, natural killer
cells) that are considered to be
a first line of immune defense
1.  Janeway CA, et al. Immunobiology: The Immune System in
Health and Disease. 6th ed. New York, NY: Garland Science;
2004.
2.  Padmanabhan RR, et al. J Leuk Biol. 1988;43:509-519.
3.  Kim R, et al. Immunology. 2007;121:1-14.
4.  Vivier E, et al. Science. 2011;331:44-49.
4
T Cells and the Anti-tumor Response
• 
• 
• 
Tumors can trigger a tumor-specific
T-cell response1-4
Multiple natural feedback
mechanisms affect immune
responses by activating or inhibiting
T-cell function and proliferation5
Tumors may evade the immune
system, in part by exploiting T-cell
activation or inhibition pathways1,2,6
–  Many immune mechanisms in the
anti-tumor response are under clinical
investigation in the treatment of cancer1,2
1. 
2. 
3. 
4. 
5. 
Pardoll DM. Nat Rev Cancer. 2012;11:252-264.
Mellman I, et al. Nature. 2011;480:480-489.
Heemskerk B, et al. EMBO J. 2013;32(2):194-203.
Boudreau JE, et al. 2011. Mol Ther. 2011;19(5):841-853.
Janeway CA, et al. Immunobiology: The Immune System in Health
and Disease. 6th ed. New York, NY: Garland Science; 2004.
6.  Dunn GP, et al. Nat Immunol. 2002;3(11):991-998.
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T Cells and the Anti-tumor Response
Tumor Antigen
Release
Tumor Antigen
Presentation to T Cells
T-Cell Activation &
Expansion
T-Cell Recognition of
Tumor Antigen
T-Cell Recognition
and Killing
6
Tumor Antigen Release
Tumor Antigen
Presentation to T Cells
T-Cell Activation &
Expansion
Tumor Antigen Release
The beginning of the anti-tumor
response: antigen-presenting cell
(APC) captures the released
tumor-associated antigens
T-Cell Recognition of
Tumor Antigen
T-Cell Recognition
and Killing
7
Tumor Antigen Release
•  Tumor-associated antigens (TAAs) can trigger a tumor-specific
T-cell response1-4
•  The initial stages of the anti-tumor immune response involve the
capture of TAAs by APCs2,4
•  After antigen capture, APCs become activated and can interact with
T cells2,4
1. 
2. 
3. 
4. 
Pardoll DM. Nat Rev Cancer. 2012;11:252-264.
Mellman I, et al. Nature. 2011;480:480-489.
Heemskerk B, et al. EMBO J. 2013;32(2):194-203.
Boudreau JE, et al. 2011. Mol Ther. 2011;19(5):841-853.
8
Tumor Antigen Presentation to T Cells
Tumor Antigen
Release
T-Cell Activation &
Expansion
Tumor Antigen
Presentation to T Cells
T-Cell Recognition of
Tumor Antigen
The APC presents tumor antigens
T-Cell Recognition
and Killing
9
T-Cell Activation in Response to Tumor
Antigen Presentation
•  APCs present the tumor-associated antigen to T cells1
•  Following antigen presentation, a second
(co-stimulatory) signal is transmitted from the APC to the T cell1
•  Co-stimulation results in T-cell activation and proliferation to initiate an
anti-tumor immune response1
1.  Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004.
10
T-Cell Activation in Response to Tumor
Antigen Presentation
•  Several T-cell activation pathways are involved in the immune
response, including1-5:
–  CD28/CD80 or CD866,7
–  CD40/CD40L7,8
–  OX40/OX40L7,9
–  CD137/CD137L7,10
1. Korman AJ, et al. Adv Immunol. 2006;90: 297-339. 2. Gruber S, et al. Anticancer Res. 2008;28: 779-784. 3. Batrla R, et al. Cancer Res.
2002;62:2052-2057. 4. Baruah P, et al. Immunobiology. 2012;217(7):669-675. 5. Wang Q, et al. Croat Med J. 2088;49:192-200. 6. Janeway
CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004. 7. Pardoll DM. Nat Rev
Cancer. 2012;11:252-264. 8. Howland KC, et al. J Immunol. 2000;164(9):4465-4470. 9. Redmond WL, et al. Crit Rev Immunol. 2009;29(3):
187-201. 10. Palazon A, et al. Cancer Res. 2011;71:801-811.
11
T-Cell Activation & Expansion
Tumor Antigen
Release
Tumor Antigen
Presentation to T Cells
T-Cell Activation &
Expansion
T-Cell Recognition of
Tumor Antigen
T-cell co-stimulation and
activation generate an effector
anti-tumor T-cell response
T-Cell Recognition
and Killing
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Inhibition of T-Cell Activation
and Expansion
•  A number of negative feedback mechanisms provide a natural
counterbalance to immune activation pathways, including1-5:
–  LAG-31,6
–  CTLA-41,7
–  B7-H31,8
1. Pardoll DM. Nat Rev Cancer. 2012;11:252-264. 2. Hemon P, et al. J Immunol. 2011,186:5173-5183. 3. Weiner Z, et al. J Investig Dermatol.
2007;127:906-914. 4. Shah KV, et al. J Invest Dermatol. 2008;128(12):2870-2879. 5. Zang X, et al. PNAS. 2007;104(49):19458-19463.
6. Workman CJ, et al. J Immunol. 2004;172(9):5450-5455. 7. Hastings WD, et al. Eur J Immunol. 2009;39(9):2942-2501. 8. Leitner J. Eur J
Immunol. 2009;39(7):1754-1764.
13
T-Cell Recognition of Tumor Antigen
Tumor Antigen
Release
Tumor Antigen
Presentation to T Cells
T-Cell Activation &
Expansion
T-Cell Recognition
of Tumor Antigen
Activated T cells migrate to
the tumor and recognize
expressed tumor antigen
T-Cell Recognition
and Killing
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T-Cell−Mediated Killing of Tumor Cells
•  T-cell co-stimulation and activation can generate a
cytotoxic (“killer”) T-cell response1
–  These tumor-specific cytotoxic T cells specifically recognize and bind to
antigens on tumor cells1
–  Cytotoxic T cells then can attack the tumor and may induce apoptosis of
the tumor cell1
1.  Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004.
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Inhibition of T-Cell Killing
• 
• 
A number of negative feedback mechanisms are involved in the
immune response
These inhibitory pathways provide a natural counterbalance to
T-cell activity, and include1:
–  LAG31,2
–  PD1/PD-L1 or PD-L21
1.  Pardoll DM. Nat Rev Cancer. 2012;11:252-264.
2.  Workman CJ, et al. J Immunol. 2004;172(9):5450-5455.
16
Tumor Evasion of the Immune System
•  While the immune system can destroy tumor cells,1,2
tumors can evolve to evade immune-mediated
clearance3,4
•  Cancer cell growth may be associated with an imbalance
in the natural feedback mechanisms (eg, immune
checkpoints) that modulate the immune response2,5
•  Understanding how immune pathways can be modulated
to overcome tumor evasion of the immune system is an
active focus of clinical research2,5
1. 
2. 
3. 
4. 
5. 
Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004.
Pardoll DM. Nat Rev Cancer. 2012;11:252-264.
Kirkwood JM, et al. CA Cancer J Clin. 2012;62:309-335.
Drake CG, et al. Adv Immunol. 2006;90:51-81.
Mellman I, et al. Nature. 2011;480:480-489.
17
Tumor Evasion Mechanisms:
T-Cell Activation & Proliferation
•  Tumors may evade the
immune system in part by
exploiting immune activation
pathways1-3
•  The presence of tumors has
been associated with
modulation of activation and
inhibitory pathways:
– 
– 
– 
– 
1. 
2. 
3. 
4. 
5. 
6. 
7. 
Pardoll DM. Nat Rev Cancer. 2012;11:252-264.
Dunn GP, et al. Nat Immunol. 2002;3(11):991-998.
Mellman I, et al. Nature. 2011;480:480-489.
Baruah P, et al. Immunobiology. 2012;217(7):669-675.
Hemon P, et al. J Immunol. 2011,186:5173-5183.
Zang X, et al. PNAS. 2007;104(49):19458-19463.
Leitner J. Eur J Immunol. 2009;39(7):1754-1764.
OX40 (activation)4
CTLA-4 (inhibitory)1
LAG-3 (inhibitory)2,5
B7-H3 (inhibitory)2,6,7
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Tumor Evasion Mechanisms:
T-Cell Activation & Proliferation, cont’d.
The presence of tumors has been associated with:
•  Decreased T-cell expression of OX40, which may inhibit the ability
to mount an effective anti-tumor response1
•  T-cell expression of CTLA-4, which inhibits the anti-tumor response
by restricting T-cell activation and proliferation2
•  Increased T-cell expression of the immune checkpoint
LAG-3, increasing the inhibition of T-cell activation and function2,3
•  Tumor cell expression of B7-H3, which may impair T-cell−mediated
immune responses, however, the precise role of B7-H3 in cancer
has not been fully elucidated2,5,6
1. 
2. 
3. 
4. 
5. 
6. 
Baruah P, et al. Immunobiology. 2012;217(7):669-67
Pardoll DM. Nat Rev Cancer. 2012;11:252-264
Hemon P, et al. J Immunol. 2011,186:5173-5183.
Kirkwood JM, et al. CA Cancer J Clin. 2012;62:309-335.
Zang X, et al. PNAS. 2007;104(49):19458-19463.
Leitner J. Eur J Immunol. 2009;39(7):1754-1764.
19
Tumor Evasion Mechanisms:
T-Cell−Mediated Killing
•  Cancer cell growth may be
associated with an imbalance in
the natural feedback mechanisms
that modulate the immune
response1,2
•  The expression of several of
these molecules is characteristic
of what has been termed
“exhausted” T cells that exhibit
reduced killing activity1
1.  Pardoll DM. Nat Rev Cancer. 2012;11:252-264
2.  Mellman I, et al. Nature.2011;480:480-489.
20
Tumor Evasion Mechanisms:
T-Cell−Mediated Killing, cont’d.
The presence of tumors has been associated with:
•  Tumor expression of PD-1 ligand (PD-L); both PD-L1
and PD-L2 bind to the PD-1 receptor on activated
T cells, which inhibits the T cells and T-cell attack1
•  Increased T-cell expression of the immune “checkpoint”
LAG-3, increasing the inhibitory effect on T-cell
activation and function2
1.  Pardoll DM. Nat Rev Cancer. 2012;11:252-264
2.  Hemon P, et al. J Immunol. 2011,186:5173-5183.
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Summary
•  The immune system continuously detects and destroys tumor cells1,2
•  One mechanism of immune clearance of tumors involves T-cell−
mediated tumor cell killing3-6
•  Tumor cells can evade immune clearance through a variety of
mechanisms1,2
–  Tumors may evade clearance by exploiting immune activation
or inhibition pathways7-9
•  A number of immune activation and inhibitory mechanisms are under
clinical investigation for their role in tumor evasion of the immune
system10-18
1. Kirkwood JM, et al. CA Cancer J Clin. 2012;62:309-335. 2. Drake CG, et al. Adv Immunol. 2006;90:51-81. 3. Janeway CA, et al.
Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004. 4. Padmanabhan RR, et al. J Leuk
Biol. 1988;43:509-519. 5. Kim R, et al. Immunology. 2007;121:1-14. 6. Vivier E, et al. Science. 2011;331:44-49. 7. Pardoll DM. Nat Rev
Cancer. 2012;11:252-264. 8. Dunn GP, et al. Nat Immunol. 2002;3(11):991-998. 9. Mellman I, et al. Nature. 2011;480:480-489. 10. Korman AJ,
et al. Adv Immunol. 2006;90: 297-339. 11. Gruber S, et al. Anticancer Res. 2008;28: 779-784. 12. Batrla R, et al. Cancer Res.
2002;62:2052-2057. 13. Baruah P, et al. Immunobiology. 2012;217(7):669-675. 14. Wang Q, et al. Croat Med J. 2088;49:192-200. 15. Hemon
P, et al. J Immunol. 2011,186:5173-5183. 16. Weiner Z, et al. J Investig Dermatol. 2007;127:906-914. 17. Shah KV, et al. J Invest Dermatol.
2008;128(12):2870-2879. 18. Zang X, et al. PNAS. 2007;104(49):19458-19463.
22
Appendix
23
Activation Pathways Involved in
T-Cell Modulation
•  CD28 binding to its ligand (CD80 [also known as B7-1] or CD86)
enhances T-cell activation via co-stimulation1-2
•  CD40 signaling promotes APC activation and enhances the
anti-tumor immune response2,3
•  OX40 (also known as CD134) promotes anti-tumor immune
responses by promoting T-cell proliferation and survival2,4
•  CD137 (also known as 4-1BB) promotes the activation and
proliferation of T cells2,5
1. 
2. 
3. 
4. 
5. 
Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004.
Pardoll DM. Nat Rev Cancer. 2012;11:252-264.
Howland KC, et al. J Immunol. 2000;164(9):4465-4470.
Redmond WL, et al. Crit Rev Immunol. 2009;29(3):187-201.
Palazon A, et al. Cancer Res. 2011;71:801-811.
24
Inhibitory Pathways Involved in
T-Cell Modulation
•  LAG-3 (also known as CD223) is an immune “checkpoint” molecule
that can inhibit T-cell activity and serves as a modulator of T-cell
activation1,2
•  CTLA-4 is an immune “checkpoint receptor” that plays a key role in
modulating T-cell function. Interaction of CTLA-4 on the T cell with
its ligands (CD80 [also known as B7-1] and CD86) on the APC leads
to
T-cell inhibition1,3
•  B7-H3, a member of the B7 family, is thought to be an immune
“checkpoint” pathway, and may inhibit the T-cell response beyond
CD80/CD86 T-cell response. The precise mechanism of B7 familymediated inhibition of T cells is under investigation1,4
•  PD-1 is an immune “checkpoint” receptor that inhibits the T-cell
response and plays a key role in modulating T-cell function1
1. 
2. 
3. 
4. 
Pardoll DM. Nat Rev Cancer. 2012;11:252-264.
Workman CJ, et al. J Immunol. 2004;172(9):5450-5455.
Hastings WD, et al. Eur J Immunol. 2009;39(9):2942-2501.
Leitner J. Eur J Immunol. 2009;39(7):1754-1764.
25