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MICa 8004 - Biology of Cancer

Biology of Cancer – MICA 8004
Spring Semester, 2014
M,W,Th,F, 9:05-9:55am, 2-580 MoosTower

Instructors:
David Largaespada (Course Director), 6-4979, larga002@umn.edu, 3-129 CCRB
Anindya Bagchi (bagch005@umn.edu)

Martina Bazzaro (mbazzaro@umn.edu)

Scott Dehm (dehm@umn.edu)
Timothy Hallstrom (halls026@umn.edu)
Ameeta Kelekar (ameeta@umn.edu)

Carol Lange (lange047@umn.edu) 

Louis Mansky (mansky@umn.edu)
Jaime Modiano (modiano@umn.edu)
Deepali Sachdev (sachd003@umn.edu)
Kaylee Schwertfeger (schwe251@umn.edu) 

Timothy Starr (star0044@umn.edu)
Douglas Yee (yeexx006@umn.edu)

Textbook
The Biology of Cancer. 2nd Edition. Robert A. Weinberg, Garland Publishing, New York, 2008.

Course Format
The course will be divided into 15 blocks consisting of 4 meetings per block. Within each block, the first two meetings will be lectures with assigned textbook chapters and/or journal articles. These lectures will cover key concepts that you will be expected to know for the final exam. Students should expect to spend time outside of class to learn techniques relevant to the assigned reading material. Course materials will be available thru a Moodle course site.

The third meeting will be a journal club-style discussion of a paper that is related to the topic of the block. Students are expected to read the entire assigned paper before class and be ready to discuss it in detail. Students will be separated into groups and each group will be expected to present part of the paper to the class. The section your group will present will not be assigned until the day of class that you present, therefore, be prepared to discuss any part of the paper. An assigned student will be the group’s spokesperson for each block – a duty that will come up approximately 3 times during the semester for each student. You will have 10 minutes with your group at the beginning of class to prepare your presentation. Presentations will be approximately 5 minutes long. These assigned groups will change three times during the course. Your group assignments will be handed out the first day of class.

The instructor will e-mail a problem-solving quiz to each student shortly after the third meeting. Students will e-mail their answers back to the instructor before the beginning of the fourth meeting, after which the instructor will present acceptable answers and lead a discussion of alternative answers and their weaknesses. The instructor will also summarize the Key Concepts of the block at the fourth meeting.

Exams
The exams will include 15 problem-solving quizzes, one per block, and a fact-based short answer format final exam. The quiz may be one essay question or multiple questions. The quizzes will be e-mailed as MS Word documents by the block instructor to the students shortly after the third meeting of each block. The completed quizzes must be e-mailed by the students back to the block instructor by the beginning of the fourth meeting. Answers must be limited to 1 page, 12pt Times New Roman font, 1-inch margins, single spacing. Answers longer than 1 page will be given a score of 0. Any material available in the scientific literature may be used to answer the questions. However, students are expected to answer their own quiz independently. None of the quiz questions may be discussed with other members of the class until after the quiz. According to criteria discussed during the fourth session, the instructor will grade each quiz, and the graded quiz will be returned to students via e-mail.

The final exam will be 1 hour in length, closed book, short answer format, and focused on the Key Concepts from each block.

Course Points
Exams - 10 points will be given for each take home quiz for a total of 150 points and 75 points will be given for the final exam.

Attendance - 5 points will be given for participation during each block for a total of 75 points. Attendance points will be based on attending all classes in each block. Attendance of all meetings is expected, with an exception for one excused absence during the course (NOT one excused absence per block). Excused absences MUST be for legitimate reasons and are to be requested from the course director, David Largaespada, when possible, before the missed meeting or immediately following.

Take Home Quizzes (15 at 10 pts each) – 150 points
Attendance Points (15 at 5 pts each block) – 75 points
Final Exam – 75 points
Total Points Available – 300

Block Topic Lecturer Group Dates (W,Th,F,M)
1 Introduction to the Course/Cancer Pathology/The TCGA Starr A Groups Jan. 22,23,24,27
2 Cancer Genetics: Cancer Viruses and Experimental Genetics Largaespada A Groups Jan. 29,30,31,Feb 3
3 Cell Signaling I: The cytoplasm (GF receptors, G-protein coupled receptors) Lange A Groups Feb. 5,6,7,10
4 Cell Signaling II: RAS, SRC, P13K, SHH, WNT, TGF Largaespada A Groups Feb 12,13,14,17
5 Cell Signaling III:  The nucleus (steroid hormone receptors, Fos/Jun, JAK-STAT) beta Dehm A Groups Feb 19,20,21,24
6 Tumor suppressor genes; Genome Instability Bagchi B Groups Feb. 26,27,28, March 3
7 RB/ Cell Cycle/P53 Hallstrom B Groups March 5,6,7,10
8/9 Apoptosis
Autophagy/Metabolism
Kelekar B Groups March 12,13,14,24,26
,27,28,31
10 Cellular Immortalization; Cancer Stem Cells Bagchi B Groups April 2,3,4,7
11 Angiogenesis Bazzaro C Groups April 9,10,11,14
12 Invasion & Metastasis Schwertfeger C Groups April 16,17,18,21
13 Cancer Therapy I: Small molecules and Targeted Therapy Sachdev/Yee C Groups April 23,24,25,28
14 Human Cancer and Microbes: Bacteria and Viruses Mansky C Groups April 30, May 1,2,5
15 Cancer Therapy II: Tumor Immunology & Immune Therapies Modiano C Groups May 7,8,9

 

Spring break March 17th -21st

MICA 8004 Reading List - Spring Semester 2014

Please read the material listed for each date BEFORE coming to class.

Block 1: Cancer Pathology

Jan. 22nd - Weinberg Chapter 1, pgs. 1-29

Jan. 23rd - Weinberg Chapter 2, pgs. 31-69

Hanahan, D. and Weinberg, R.A. Hallmarks of Cancer: The Next Generation. 2011. Cell 144,
646-674.

Jan. 24th - A Molecularly Annotated Platform of Patient-Derived Xenografts (''Xenopatients'')
Identifies HER2 as an Effective Therapeutic Target in Cetuximab-Resistant Colorectal Cancer. Andrea Bertotti, Giorgia Migliardi, Francesco Galimi, et al.
Cancer Discovery 2011;1:508-523. Published OnlineFirst September 2, 2011.

Jan. 27th – (additional readings, not required)

David, A.R. and Zimmerman, M.R. Cancer: an old disease, a new disease or something
inbetween? 2010. Nature Reviews: Cancer. Vol. 10, 728-733.

Faltas, Bishoy. Cancer is an ancient disease: the case for better palaeoepidemiological and
molecular studies. 2010 Nature Reviews: Cancer. Response.

Block 2: Cancer Genetics: Cancer Viruses and Experimental Genetics

Jan. 29th - Weinberg Chapter 3, read the Synopsis, Prospects, & Key Concepts pp. 86-90. Skim the
chapter and read the bolded words/terms. If you understand key concepts and bolded word/terms, no further reading required.

Jan. 30th - Weinberg Chapter 4, read the Synopsis, Prospects, & Key Concepts pp. 112-116. Skim the
chapter and read the bolded words/terms. If you understand key concepts and bolded word/terms, no further reading required.

Jan. 31st - Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H,
Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008 Sep 26; 321 (5897):1807-12.

Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, Edwards CR, Khanin R, Figueroa ME, Melnick A, Wellen KE, O'Rourke DM, Berger SL, Chan TA, Levine RL, Mellinghoff IK, IDH mutation impairs histone demethylation and results in a block to cell differentiation. Thompson CB. Nature. 2012 Feb 15; 483n (7390):474-8.

Feb. 3rd – (additional readings, not required)

Read "The Emperor of All Maladies: A Biography of Cancer" by Siddhartha Mukherjee.

Block 3: Cell Signaling I: The Cytoplasm (GF Receptors, G-Protein Coupled Receptors)

Feb 5th – Weinberg Chapter 5 – Kinases and Kinase Receptors (integrin receptors will be covered
elsewhere)

Feb 6th – Weinberg Chapter 5 cont. – Passing the signal: Ras and Downstream Signaling to MAP
Kinase Cascades

Required reading (short reviews):
Ferrell JE Jr. What do scaffold proteins really do? Sci STKE. 2000 Oct 3;2000 (52):PE1. Review.

Neuzillet C, Tijeras-Raballand A, de Mestier L, Cros J, Faivre S, Raymond E. MEK in cancer and cancer therapy. Pharmacol Ther. 2013 Oct 9. pii: S0163-7258(13)00206-4.

Polivka J Jr, Janku F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther. 2013 Dec 9. pii: S0163-7258(13)00240-4.

Optional Review Article:
Koul HK, Pal M, Koul S. Role of p38 MAP Kinase Signal Transduction in Solid Tumors. Genes Cancer. 2013 Sep;4(9-10):342-359. Review.

Feb 7th - Ras signaling specificity in cancer biology - Discuss Gupta paper in class.

AR Ramjaun and J Downward. Ras and Phosphoinositide 3-Kinase: Partners in Development and Tumorigenesis. Cell Cycle 6:23, 2902-2905, 2007

S Gupta et. al (Julian Downward lab). Binding of Ras to PI3K p110a is required for Ras-driven tumorigenesis in mice. Cell 129: 957-968, 2007.

Feb 10th - (additional readings, not required)

Translating the strength and duration (i.e. specificity) of the signal into changes in cell biology:
Murphy LO and Blenis J. MAPK signal specificity: the right place at the right time. TRENDS in Biomedical Sciences 2006: 31(5): 268-275.

Signaling Kinetics: What can a 3-kinase cascade do?:
Huang CY, Ferrell JE Jr. Ultrasensitivity in the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10078-83.

Nucleo-cytoplasmic transport in signaling (yet another mechanism of signaling specificity…):
James E. Ferrell, Jr. How regulated protein translocation can produce switch-like responses. TIBS 23: 461-465, 1998.

Chahine MN, Pierce GN. Therapeutic targeting of nuclear protein import in pathological cell conditions. Pharmacol Rev. 2009 Sep;61(3):358-72. Review. (Good background and relevance to cancer therapy)

Block 4: Cell Signaling II: RAS, SRC, P13K, SHH, WNT, TGFbeta

Feb. 19th - Wienberg Chapter 6, pgs. 175-202

Feb. 20th - Wienberg Chapter 6, pgs. 206-228

Feb. 21st - Yan Wang,Qingqing Ding,Chia-Jui Yen, et. al. The Crosstalk of mTOR/S6K1 and
Hedgehog Pathways. Cancer Cell, Volume 21, Issue 3, 374-387, 20 March 2012

Feb. 24th – (additional readings, not required)

Cancer Cell. 2012 Nov 13;22(5):571-84. doi: 10.1016/j.ccr.2012.08.013. Dependency of
Colorectal Cancer on a TGF-β-Driven Program in Stromal Cells for Metastasis Initiation.Calon A, Espinet E, Palomo-Ponce S, Tauriello DV, Iglesias M, Céspedes MV, Sevillano M, Nadal C, Jung P, Zhang XH, Byrom D, Riera A, Rossell D,Mangues R, Massagué J, Sancho E, Batlle E.

Cancer Cell. 2012 Nov 13;22(5):668-82. doi: 10.1016/j.ccr.2012.10.009. Relief of Profound Feedback Inhibition of Mitogenic Signaling by RAF Inhibitors Attenuates Their Activity in BRAFV600E Melanomas. Lito P, Pratilas CA, Joseph EW, Tadi M, Halilovic E, Zubrowski M, Huang A, Wong WL, Callahan MK, Merghoub T, Wolchok JD, de Stanchina E,Chandarlapaty S, Poulikakos PI, Fagin JA, Rosen N.

Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells. Muranen T, Selfors LM, Worster DT, Iwanicki MP, Song L, Morales FC, Gao S, Mills GB,Brugge JS. Cancer Cell. 2012 Feb 14;21(2):227-39.

Block 5: Cell Signaling III: The Nucleus (Steroid Hormone Receptors, Fos/Jun, JAK-STAT)

Feb. 12th - Weinberg Chapter 1.6, 1.7, 1.8, and Weinberg Chapter 6.1, 6.5, 6.6, 6.8, 6.10, 6.12 (these
should already have been read in preparation for previous Blocks)

Chi P, Allis DC, Wang GG. Covalent histone modifications—miswritten, misinterpreted and mis-erased in human cancers. Nature Reviews Cancer 10:457-469, 2010.

Feb. 13th - Jozwik KM, Carroll JS. Pioneer factors in hormone-dependent cancers. Nature Reviews
Cancer. 12:381-385, 2012.

Feb. 14th - Hurtado A, Holmes KA, Ross-Innes CS, Schmidt D, Carroll JS. FOXA1 is a key
determinant of estrogen receptor function and endocrine response. Nature Genetics 43:27-33, 2011.

Feb. 17th – (additional readings, not required)

Cheung E and Ruan Y. Determination of transcription factor binding. Nature Genetics 43: 11-12, 2011.

Ross-Innes CR et al., Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature 481: 389-93, 2012.

Cowper-Sal L et al., Breast cancer risk-associated SNPs modulate the affinity of chromatin for FOXA1 and alter gene expression. Nature Genetics 44:1191-1198, 2012.

Block 6: Tumor Suppressor Genes, Genome Instability

Feb. 26th - Weinberg Chapter 7, pgs. 209-254

Feb. 27th - Weinberg Chapter 12, pgs. 463-526

Feb. 28th - The Landscape of Microsatellite Instability in Colorectal and Endometrial Cancer Genomes
Cell, Volume 155, Issue 4, 7 November 2013, Pages 858–868

March 3rd – (additional readings, not required)
None

Block 7: RB/Cell Cycle/P53

March 5th - Weinberg Chapter 8

March 6th - Weinberg Chapter 9.1-9.12

March 7th - Skp2 deletion unmasks a p27 safeguard that blocks tumorigenesis in the absence of pRb and p53 tumor suppressors. Cancer Cell. 2013 Nov 11;24(5):645-59

March 10th – (additional readings, not required)

The Rb/E2F pathway: expanding roles and emerging paradigms. J. William Harbour and Douglas C. Dean

Tumor suppression by Ink4a-Arf: progress and puzzles. Scott W. Lowe and Charles J Sherr

E2f1–3 switch from activators in progenitor cells to repressors in differentiating cells. Jean-Leon Chong et. al. (Gustavo Leone Lab)

Block 8/9: Apoptosis Autophagy/Metabolism

March 12th - Ola, M.S., M. Nawaz, and H. Ahsan, Role of Bcl-2 family proteins and caspases in the
regulation of apoptosis. Mol Cell Biochem, 2011. 351(1-2): p. 41-58

Additional Reading (optional) - Youle, R.J. and A. Strasser, The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol, 2008. 9(1): p. 47-59

March 13th - Mizushima, N. and M. Komatsu, Autophagy: renovation of cells and tissues. Cell, 2011.
147(4): p. 728-741

March 14th - Cantor, J.R. and D.M. Sabatini, Cancer cell metabolism: one hallmark, many faces.
Cancer Discov, 2012. 2(10): p. 881-898

Additional Reading (optional) - Leone, R.D. and R.K. Amaravadi, Autophagy: a targetable linchpin of cancer cell metabolism. Trends Endocrinol Metab, 2013. 24(4): p. 209-217.

March 24th – None

March 26th – None

March 27th - Son, J., C.A. Lyssiotis, H. Ying, et al., Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature, 2013. 496(7443): p. 101-105.This is
the date for Block 8 spokespersons.

March 28th - Willems, L., N. Jacque, A. Jacquel, et al., Inhibiting glutamine uptake represents an
attractive new strategy for treating acute myeloid leukemia. Blood, 2013. 122(20): p. 3521-3532. This is the date for Block 9 Spokespersons.

March 31st – None

Block 10: Cellular Immortalization; Cancer Stem Cells

April 2nd - Weinberg Chapter 10, pgs. 357-398

April 3rd - Weinberg Chapter 11, pgs. 399-441

April 4th - Brd4 and JMJD6-Associated Anti-Pause Enhancers in Regulation of Transcriptional Pause
Release Cell 155, 1581–1595, December 19, 2013

April 7th – (additional readings, not required)
None

Block 11: Angiogenesis

April 9th - Weinberg Chapter 13

April 10th – Weinberg Chapter 13

April 11th - TBD

April 14th – (additional readings, not required)
TBD

Block 12: Invasion and Metastasis

April 16th - Weinberg Chapter 14 pgs. 641-685

April 17th - Weinberg Chapter 14 pgs. 686-689, 695-719

April 18th - Tumor-induced osteoclast miRNA changes as regulators and biomarkers of osteolytic bone
metastasis. Ell et al., Cancer Cell 24(4), 542-556, 2013.

April 21st – (additional readings, not required)
None

Block 13: Cancer Therapy I: Small Molecules and Targeted Therapy

April 23rd - Wienberg Chapter 16 pgs. 797-815

April 24th - Wienberg Chapter 16 pgs. 815-818; 825-833; 844-860

April 25th - TBD

April 28th – (additional readings, not required)
None

Block 14: Human Cancer and Microbes: Bacteria and Viruses

April 30th - Weinberg Chapter 11

May 1st - TBD

May 2nd - TBD

May 5th– (additional readings, not required)
TBD

Block 15: Cancer Therapy II: Tumor Immunology and Immune Therapies

May 7th – Weinberg Chapter TBD

May 8th - The first 8 short articles of the Outlook Supplement to the last issue of Nature in 2013 (Nature 504, S2–S17 (19 December 2013) and the Breakthrough of the Year article in Science (Science Vol 342:1432-1433 (20 DECEMBER 2013).

May 9th - TBD

 

MICA 8004 – Biology of Cancer
Key Concepts

Block 1: Cancer Pathology and the TCGA
1. Use and understand terminology describing pathological and molecular processes in cancer development and progression
2. Enumerate and provide an overview of the hallmarks of cancer and their significance to diagnosis and therapy
3. Discuss changes in the dynamics of cancer incidence and prevalence in the past 3-5 decades (i.e.,
answer the question, “is there a cancer epidemic?”)
4. Describe the histological origins of cancer and their relationship to processes of developmental biology

Block 2: Cancer Genetics: Cancer Viruses, Experimental Genetics
1. The discovery of oncogenes
2. Mechanisms that create oncogenes
3. Genetically engineered mouse models: A) Transgenic mice and B) Knock-out/Knock-in mice
4. The tumor genome – capabilities and limitations

Block 3: Cell Signaling I: The Cytoplasm (GF Receptors, G-Protein Coupled Receptors)
1. Tryrosine kinase growth factor receptors and their ligands
2. G-Protein coupled receptors/serpentine receptors
3. Introduction to G-proteins (small G-proteins vs heterotrimeric)
4. Functional consequences of 3-kinase cascades (ERK/MAPK signaling)
5. Mechanisms of signaling specificity
6. Mechanisms of resistance to targeted therapies (against receptors)

Block 4: Cell Signaling II: RAS, SRC, P13K, SHH, WNT, TGFbeta
1. Regulation of small GTPases by GEFs and GAPs
2. Assembly of signaling complexes involving SH2 and SH3 domain containing proteins
3. PI3K signaling as a master regulator of cancer development and maintenance
4. Signal pathway regulation by a destruction complex
5. The paradoxical role of TGF-beta in cancer development and progression
6. Feedback signal pathway regulation in cancer cell signaling

Block 5: Cell Signaling III: The Nucleus (Steroid Hormone Receptors, Fos/Jun, JAK-STAT)
1. Transcription and deregulation in cancer
2. Fos/Jun, STATs and oncogenic signal transduction pathways
3. Hormone receptors and the development and progression of prostate and breast cancers.
4. Androgen and estrogen signaling pathways, “molecularly targeted therapies” and resistance

Block 6: Tumor Suppressor Genes: Genome Instability
1. Mechanisms for loss of heterozygoisity (LOH) during tumorigenesis
2. DNA repair mechanisms are tumor suppressive
3. Base excision repair
4. Mismatch repair
5. Homologous recombination

Block 7: RB/Cell Cycle/P53
1. The cell cycle, cyclins and their catalytic CDK binding partners
2. Timing and signals of cell fate, such as growth, quiescence, apoptosis, differentiation or senescence
3. E2F transcription factors associated with promoters of genes that control cell cycle, DNA replication and mitosis.
4. Hypophosphorylated pRb and hyperphosphorylated pRb
5. Loss of pRb function
6. Inactive pRb and activation of pro-apoptotic or senescence programs.

Block 8/9: Apoptosis /Autophagy/Metabolism
1. Programmed Cell Death and Apoptotic pathways in normal cells and their aberrant regulation in cancer, with special emphasis on the involvement of the Bcl-2 family of proteins
2. Autophagy as a Stress Response in normal cells, and the contradictory and contextual roles for deregulated Autophagy in tumor suppression and tumor progression
3. The Warburg Hypothesis and Metabolic Reprogramming in actively proliferating normal cells and cancer cells
4. Apoptosis, Autophagy and Metabolism are closely linked – understanding the crosstalk, the overlap and the shared regulators

Block 10: Cellular Immortalization; Cancer Stem Cells
1. Telomeres, the end replication problem, and immortalization
2. Mortality limits: senescence and crisis
3. Breakage-bridge-fusion cycles and genome instability
4. The concept of tumor target cells, as tissue stem cells, during cancer development
5. What is a cancer stem cell?

Block 11: Angiogenesis
1. Tumors and intercommunication between various cell types
2. The recruitment of macrophages, fibroblasts and fibroblast and their key roles during tumor-associated angiogenesis
3. The “Angiogenic switch” and tumor-associated angiogenesis as a critical determinant of tumor growth.
4. Neo-angiogenesis as target for development of novel anticancer agents as angiogenesis inhibitors are designed to “cut off cancer’s supplies”

Block 12: Invasion and Metastasis
1. Metastatic cascade steps including 1) local invasion, 2) intravastion, 3) transport, 4) extravasation, 5) formation of micrometastases and 6) colonization
2. The process of epithelial-mesenchymal transition (EMT), during which epithelial gene expression is lost and mesenchymal gene expression is gained, contributes to tumor cell motility and invasiveness
3. MMPs promote invasion by degrading the basement membrane and releasing growth and angiogenic factors from the extracellular matrix.
4. Metastasis involves changes in the tumor cells and contributions from stromal/host cells both within the local microenvironment and at distant sites

Block 13: Cancer Therapy I: Small Molecules and Targeted Therapy
1. Understand the role of systemic therapy in reducing breast cancer deaths.
2. Identifying prognostic factors and their roles as targets for cancer therapy.
3. Describe the role for targeted therapies and mechanism of action.
4. Resistance to targeted therapies is frequently seen and can be either de novo or acquired. Understand that targeting multiple pathways may be critical.

Block 14: Human Cancer and Microbes: Bacteria and Viruses
1. Viruses and bacteria can cause human cancer. Roughly 20% of human cancer has a viral etiology.
2. Microbes are incomplete carcinogens, often cause chronic inflammation leading to cancer.
3. Viral proteins designed to enhance replication can contribute to cancer development.
4. Criteria for establishing causation differs from Koch’s postulates

Block 15: Cancer Therapy II: Tumor Immunology and Immune Therapies
1. Describe how immune surveillance constantly eliminates nascent tumors and understand the notion that, by definition, cancer has escaped immune surveillance.
2. Enumerate the features of the immune system that make it attractive to exploit for cancer therapy: specificity, memory, and the ability of immune cells to reach every part of the body that is inaccessible to conventional therapies.
3. Discuss reasons why monoclonal antibody therapy is the immune-based approach that has had the most profound effect in cancer therapy to date.
4. Discuss why overcoming cancer-mediated immune suppression is critical for the success of cell-based immune therapies.