CD8+ T Cells Need a Little Help(er) for Sustained Antitumor Response

The first graphic shows CD8+ immune cells travel from lymph node and try to eliminate tumor cells, but are only partially successful, because the body begins to tolerate the tumor. The second graphic shows how sustained signaling from CD4+ 'help' immune cells prevents tolerance of the tumor, alters the microenvironment, and stimulates other immune cells to join the CD8+ cells in their attack on tumor.

The first graphic shows CD8+ immune cells travel from lymph node and try to eliminate tumor cells, but are only partially successful, because the body begins to tolerate the tumor. The second graphic shows how sustained signaling from CD4+ "help" immune cells prevents tolerance of the tumor, alters the microenvironment, and stimulates other immune cells to join the CD8+ cells in their attack on tumor.

The immune system comprises a powerful army of specialized cells and molecules that protect the body against invading foreign agents. For years, researchers have been trying to find a way to turn the wrath of the immune system against cancer. A significant amount of work related to cancer immunotherapy has focused on the potential of CD8+ cytotoxic T cells to attack and eliminate cancer cells. However, this approach has proved challenging for two reasons. First, there are several mechanisms in place to make sure that T cells and other components of the immune system ignore “self” molecules and cells, even if these cells become cancerous. Second, tumor microenvironments are often characterized by the presence of immunosuppressive factors capable of stifling T cell activation (a process called tolerization).

 

Researchers in the CCR Cancer and Inflammation Program have been studying the interactions between the immune system and tumors to try to find a way to overcome the tolerance of the immune system to cancer. Kimberly Shafer-Weaver, Ph.D., and Stephanie Watkins, Ph.D., working in the laboratory of Arthur Hurwitz, Ph.D., recently coauthored a publication in Cancer Research showing that the addition of helper T cells to a mouse model of prostate cancer could prevent tolerization of the immune system to tumor cells.

The TRAMP mouse model—which develops prostate cancer as a result of prostate-targeted oncogene overexpression—was used for these studies. Previous studies had shown that the TRAMP prostate tumor microenvironment was able to squelch the activity of CD8+ T cells primed to attack the tumor. Shafer-Weaver and Watkins decided to use another type of T cell—CD4+ helper T cells—to try to overcome this tolerization. CD4+ helper T cells are known to produce signaling molecules and activate accessory immune cells that help establish and maintain effective CD8+ cytotoxic T cell responses.

To find out whether CD4+ helper T cell could enhance the antitumor activity of CD8+ cytotoxic T cells, TRAMP mice were injected with both tumor-specific helper T and cytotoxic T cells. The initial results were encouraging—activation of the CD8+ cells was enhanced. However, the results were short-lived. Within 20 days, both CD4+ and CD8+ cytotoxic T cells had become tolerized by the tumor microenvironment and were no longer functional.

Encouraged by the transient effect, Shafer-Weaver and Watkins carried out another experiment in which TRAMP mice were given multiple injections of tumor-specific CD4+ helper T cells over time. This consistent influx of the helper T cells was able to prevent the tolerization of CD8+ T cells in the prostate tumor microenvironment. Activity of the CD8+ T cells persisted for up to 30 days after injection and resulted in a significant reduction in prostate tumor burden. Additional analysis revealed that the effect was due at least in-part to helper T cell activation of antigen presenting cells (which promote cytotoxic T cell activation) within the prostate tumor microenvironment.

Taken together, these results indicate that the sustained presence of CD4+ helper T cells can alter the tumor microenvironment to promote cytotoxic T cell activation and antitumor immune response. These insights should contribute to the development of novel approaches to eliminate T cell tolerance to tumor cells and improve the effectiveness of cancer immunotherapies.

Summary Posted: 08/2009

Reference

Cancer Res. 2009 Jul 21. [Epub ahead of print] PubMed Link