Three Exciting Concepts in Tumor Immunology and Immunotherapy

Report from the Inflammation, Infection, and Cancer and Immune Evolution in Cancer Joint Keystone Symposia, March 9-14, 2014 at Whistler, BC. These symposia focused primarily on the development and immunology of solid tumors. However, there were some very interesting discussions about progress in the treatment of B-CLL and other hematopoietic tumors. 

The mechanisms of survival and progression of solid tumors can be loosely divided into two types: those that affect the tumor itself, and those that affect the immune response to the tumor. Chronic, sub-clinical, asymptomatic inflammation is a conducive microenvironment for tumor development. The effect of tumor factors is contextual and obviously complicated. Factors affecting tumor progression vary from tissue to tissue, tumor to tumor, and individual to individual. Tumors are very good at suppressing immune response, and have evolved multiple mechanisms with which to accomplish this. Some mechanisms may be passive, and some more aggressive. Each different mechanism is quite intricate. As a result there is no one-size-fits-all therapy. Successful treatment requires finding the dominant mechanism in each patient and each tumor. Immunological selection also is involved in tumor establishment and progression. As one investigator put it, we can’t control all the mechanisms, but we can try to control the major ones and hope the rest fall in line.

Following are the three concepts that I found most exciting from the meeting.

1. The tumor vasculature appears to block the infiltration of CD8 T cells into the core of the tumor. Infiltration of CD8 T cells is critical for maintaining tumor “stasis”. In some cases T cells become activated, but can’t infiltrate the tumor.Tumor barrier Several mechanisms by which tumor vasculature can restrict or block access to the core of the tumor were discussed. One possible mechanism that has been observed is that ADAM17 on the surface of Myeloid Derived Suppressor Cells (MDSCs) cleaves L-selectin from the surface of T cells, preventing extravasation of CD8 T cells and entry into the tumor. HMGB1 inhibition decreases ADAM17 on MDSCs and restores L-selectin expression on T cells, providing an opportunity for therapeutic intervention. [Suzanne Ostrand-Rosenberg (1)]. In other cases, tumor endothelial cells have been shown to express FASL on their surfaces. Contact of infiltrating T cells expressing FAS with FASL-expressing tumor vasculature thus leads to death of the T cells when they reach the endothelium. [G. Coukos, (2,3)].

Vascular targeting

2. Targeting cytokines locally. With regard to cytokines, some work which I found particularly exciting was the specific targeting of cytokines to tumor vasculature using the vascular homing peptide RGR conjugated to a cytokine.  (RGR peptide has been shown to associate with angiogenic vessels, 4). This approach results in a more localized effect requiring much less cytokine than systemic administration.  For example, IL-2-RGR leads to prolonged T cell survival within tumors, and primes other immune cells locally. This approach also may be useful for adoptive cell therapy. Another potential and extremely clever use of targeted cytokine therapy is to induce the development of HEV within a tumor essentially creating an ectopic lymph node within the tumor. This would involve the use of the cytokine LIGHT coupled to RGR. [R. Ganss (5)]

3. Adoptive T Cell therapy  with CAR-expressing T cells. Adoptive T Cell Therapy uses ex vivo-activated autologous T cells engineered to express an artificial chimeric antigen receptor (CAR).  CARs target the T cells and their effector functions to specific tumor antigens.  CAR T cellsCAR T Cell Adoptive Immunotherapy has been used successfully for treatment of B-CLL and other hematopoietic tumors, and is currently being evaluated for the treatment of solid tumors. [C. June (6,7)].

Closing Comments

Each individual tumor is unique and shaped by our immune response, which is itself unique to us, and by the initiating mutation or mutations. There are as many mechanisms as there are tumors, and the effect of tumor factors is contextual. However, each mechanism of tumor promotion, escape from the immune system, and metastasis provides a unique opportunity for therapeutic intervention and treatment. The most effective treatments will most likely involve a combination of targets unique to a particular tumor or family of tumors. We may need to treat underlying inflammation, as well as targeting the tumor stroma and vasculature as well as the tumor cells themselves and modulating the immune response. █

1. Hanson EM, Clements VK, Sinha P, Ilkovitch D, and Ostrand-Rosenberg S. 2009. Myeloid-Derived Suppressor Cells Down-Regulate L-Selectin Expression on CD4+ and CD8+ T Cells. J Immunol. 183(2): 937–944.

2. Sata, M. and Walsh, K. 1998. TNFa regulation of Fas ligand expression on the vascular endothelium modulates leukocyte extravasation. Nature Med. 4: 415–420.

3. Sata M, Luo Z, and Walsh K. 2001. Fas Ligand Overexpression on Allograft Endothelium Inhibits Inflammatory Cell Infiltration and Transplant-Associated Intimal Hyperplasia. J. Immunol. 166: 6964-6971.

4. Joyce JA, Laakkonen P, Bernasconi M, Bergers G, Ruoslahti E, and Hanahan D. 2003. Stage-specific vascular markers revealed by phage display in a mouse model of pancreatic islet tumorigenesis. Cancer Cell 4: 393–403.

5. Johansson A, Juliana Hamzah J, Payne CJ, and Ganss R. 2012. Tumor-targeted TNFα stabilizes tumor vessels and enhances active immunotherapy. PNAS 109 (20): 7841–7846.

6. Porter DL, Levine BL, Kalos M, Bagg A, June CH. 2011. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 365 (8): 725-33.

7. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH. 2013. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 368 (16):1509-18.

Author: Steve Anderson, Ph.D.

Steve Anderson has a Ph.D. in Immunology with over 25 years experience in biomedical research. His scientific expertise includes immunology, immunological diseases, tumor immunology, virology, and HIV pathogenesis.