Identification of Novel Mechanism for Suppression of Antitumor Immunity


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The efficacy of cancer immunotherapy has been limited, likely reflecting in large part the incomplete understanding of the complex interactions between tumors and the immune microenvironment. A study presented at the 2012 ASCO Annual Meeting helps clarify some of these interactions.

Changes in Tumor Microenvironment

Brent A. Hanks, MD, PhD, and colleagues at Duke University Medical Center in Durham, North Carolina, have found that progression in several types of tumors is accompanied by downregulation of expression of the type III transforming growth factor β (TGFβ) receptor TβRIII; the receptor is shed from the cell surface to form soluble TβRIII (sTβRIII), which is capable of sequestering TGFβ. These investigators have now shown that the loss of TβRIII expression is associated with a reduction in tumor infiltrating CD8-positive T cells and an increase in regulatory T cells in the tumor microenvironment in both breast cancer and melanoma tumor models.1 The data imply that these changes correlate with suppression of tumor antigen-specific T-cell responses and more rapid disease progression.

Synergy of TGFβ Inhibition and HER2/neu Vaccine

These changes have been shown to be associated with increased TGFβ signaling within the immune compartment of the tumor microenvironment, resulting in increased expression of indoleamine 2,3-dioxygenase immunoregulatory enzyme by local plasmacytoid dendritic cells and regulatory T-cell–recruiting CCL22 chemokine by local myeloid dendritic cells. Microarray analysis has indicated that the associated changes in gene expression also occur in human breast cancers. Consistent with these findings, Dr. Hanks and colleagues have shown that inhibition of TGFβ synergistically enhances the antitumor effect of a HER2/neu vaccine in a breast cancer model; further, they have found that plasma levels of sTβRIII are correlated with clinical response and overall survival in stage III melanoma patients.

The investigators stated, “We have elucidated a novel mechanism that tumors utilize to suppress the generation of antitumor immunity by establishing a link between the loss of an endogenous suppressor of tumor metastasis, TβRIII, and the generation of an immunotolerant tumor microenvironment.”

Additional Studies

When asked to comment on the implications of these findings, Dr. Hanks stated, “I would emphasize that additional studies still need to be completed to determine the significance of this immune evasion mechanism in human tissues. However, we are encouraged that we are seeing very similar results in both breast cancer and melanoma tumor models. This mechanism links intrinsic changes in the genetic makeup of the tumor with an altered dendritic cell phenotype that effectively dampens the generation of targeted antitumor immunity.”

He continued, “The data strongly suggest that combining a TGF-beta inhibitor with another immunotherapy approach has significant potential. As a result, we are pursuing additional preclinical studies to better optimize this strategy for future early phase clinical trials. Further, since the process we have identified involves a soluble protein, measuring this protein in patient plasma may enable us to better understand the immunology of the tumor microenvironment. Additional work investigating the usefulness of sTβRIII as a clinical biomarker is ongoing.” ■

Disclosure: Dr. Hanks reported no potential conflicts of interest.

Reference

1. Hanks BA, Holtzhausen A, Gimpel P, et al: Effect of the loss of the type III TGFβ receptor during tumor progression on tumor microenvironment: Preclinical development of TGFβ inhibition and TGFβ-related biomarkers to enhance immunotherapy efficacy. 2012 ASCO Annual Meeting. Abstract 10563. Presented June 4, 2012.



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