Cell-Intrinsic Abrogation of TGF-β Signaling Delays but Does Not Prevent Dysfunction of Self/Tumor-Specific CD8 T Cells in a Murine Model of Autochthonous Prostate Cancer

Abstract

Adoptive T cell therapy (ACT) for the treatment of established cancers is actively being pursued in clinical trials. However, poor in vivo persistence and maintenance of anti-tumor activity of transferred T cells remain major problems. Transforming growth factor beta (TGFβ) is a potent immunosuppressive cytokine that is often expressed at high levels within the tumor microenvironment, potentially limiting T cell mediated anti-tumor activity. Here, we used a model of autochthonous murine prostate cancer to evaluate the effect of cell intrinsic abrogation of TGFβ signaling in self/tumor specific CD8 T cells used in ACT to target the tumor in situ. We found that persistence and anti-tumor activity of adoptively transferred effector T cells deficient in TGFβ signaling was significantly improved in the cancerous prostate. However, over time, despite persistence in peripheral lymphoid organs, the numbers of transferred cells in the prostate decreased and the residual prostate infiltrating T cells were no longer functional. These findings reveal that TGFβ negatively regulates the accumulation and effector function of transferred self/tumor specific CD8 T cells and highlight that, when targeting a tumor antigen that is also expressed as a self-protein, additional substantive obstacles are operative within the tumor microenvironment, potentially hampering the success of ACT for solid tumors.

Blockade of TGF-β Signaling Greatly Enhances the Efficacy of TCR Gene Therapy of Cancer

“…In contrast to the profound antitumor effect of adoptive cell transfer and TGF-b blockade in this study, Chou et al (36) have recently observed that adoptively transferred T cells derived from OT-I TGFbRII knockout mice display only limited antitumor effects and are rendered tolerant in a mouse model of autochthonous prostate cancer. One clear difference between these studies is that in our study a cancer-driving Ag was the target of adoptively transferred T cells, whereas Chou et al (36) targeted an Ag that did not play a role in tumor development or the maintenance of the malignant phenotype.…”

“…One clear difference between these studies is that in our study a cancer-driving Ag was the target of adoptively transferred T cells, whereas Chou et al (36) targeted an Ag that did not play a role in tumor development or the maintenance of the malignant phenotype. Therefore, the likelihood of the emergence of tumor Ag loss variants would have been greater in the study by Chou et al (36), but whether tumor Ag loss variants occurred in their study was not directly addressed.…”

“…One clear difference between these studies is that in our study a cancer-driving Ag was the target of adoptively transferred T cells, whereas Chou et al (36) targeted an Ag that did not play a role in tumor development or the maintenance of the malignant phenotype. Therefore, the likelihood of the emergence of tumor Ag loss variants would have been greater in the study by Chou et al (36), but whether tumor Ag loss variants occurred in their study was not directly addressed. Another major difference between these studies is that the mice in our study received a lymphodepleting preconditioning regimen prior to the adoptive transfer of T cells, whereas no such regimen was used in the study by Chou et al (36).…”

“…Therefore, the likelihood of the emergence of tumor Ag loss variants would have been greater in the study by Chou et al (36), but whether tumor Ag loss variants occurred in their study was not directly addressed. Another major difference between these studies is that the mice in our study received a lymphodepleting preconditioning regimen prior to the adoptive transfer of T cells, whereas no such regimen was used in the study by Chou et al (36). Lymphodepleting preconditioning regimens are routinely used prior to adoptive cell transfer in the clinical setting (5-7), and studies in mice have demonstrated the crucial role this process plays in promoting the in vivo function of adoptively transferred T cells (48)(49)(50).…”

“…Prior studies have described TGF-b-mediated immune suppression in mouse tumor models (28)(29)(30)(31), and studies have shown that T cells engineered to be insensitive to TGF-b signaling display enhanced antitumor efficacy in mouse transplantable tumor models (32)(33)(34) and inhibit tumor development in autochthonous mouse tumor models (35). In contrast though, short-term experiments at a clinically more relevant time point in autochthonous mouse tumor models have not yielded encouraging data (36).…”