1. Cancer and the Immune Response

3. Tumors are Immunogenic. Altered-self model.

4. Altered peptide can bind now MHC Same peptide has new epitope bind

5. Immunoediting "The rabbit runs faster than the fox, because the rabbit is running for his life while the fox is only running for his dinner." Aesop [10]Aesop [10] Red Queen

6. Down-regulation of class I MHC on tumor cell calls in NK cells (next slide)

8. Don’t forget the online class evaluation!

9. Cancer Immunotherapy “In 1891, William B. Coley injected streptococcal organisms into a patient with inoperable cancer. He thought that the infection he produced would have the side effect of shrinking the malignant tumor. He was successful, and this was one of the first examples of immunotherapy. Over the next forty years, as head of the Bone Tumor Service at Memorial Hospital in New York, Coley injected more than 1000 cancer patients with bacteria or bacterial products. These products became known as Coley's Toxins. He and other doctors who used them reported excellent results, especially in bone and soft-tissue sarcomas.” http://www.ncbi.nlm.nih.gov/pmc/article s/PMC1888599/

10. Tumor-infiltrating lymphocytes in human colorectal carcinoma

11. TILs in tumor at resection correlates with prognosis

12. Anti-CD47 antibody–mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response Diane Tsenga, Jens-Peter Volkmera, Stephen B. Willingham, Humberto Contreras-Trujillo, John W. Fathmana, Nathaniel B. Fernhoff, Jun Seitaa, Matthew A. Inlaya, Kipp Weiskopf, Masanori Miyanishia, and Irving L. Weissman. Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Cancer Center, Stanford University Medical Center, Stanford, CA 94305 Contributed by Irving L. Weissman, April 4, 2013 (sent for review February 12, 2013)

13. Cancer turkey Hungry macrophage CTL proliferation

14. Innate response Adaptive response (cross presentation) Cancer cells upregulate CD-47 Apoptotic cells express “eat me” signal”

15. CD-47 upregulation creates an “invisibility cloak” for cancer cells.

16. Macrophages. Labeled with red fluorescent protein. Colon cancer cells (DLD1). Transfected with OVA-GFP. T cells OT-I – CD8+; transgenic for OVA-specific TCR OT-II – CD4+; transgenic for OVA-specific TCR Monoclonal antibodies against CD47 B6H12 (blocking) 203 (non blocking) Ig (control)

17. Macrophages phagocytose cancer cells when CD47 blocked. Not true of dendritic cells. 1

18. CFSE dilution assay

19. A) Macrophages activate (prime) OVA-specific CD8 + T-cells to proliferate after phagocytosis of OVA cells. B) Proliferation is antigen specific. 2

20. Macrophages do not activate (prime) OVA-specific CD4 + T-cells (OT-II) to proliferate after phagocytosis of OVA cells 3 OVA 323-339 control

21. T regs are reduced after phagocytosis 4

22. CTL Proliferation also occurs in vivo 5

23. Macrophages can activate CD8+ cells in vivo and transfer both T cell proliferation and tumor cell killing