In our previous work, we have identified a population of T-reg, tumor-associated CD4+ “regulatory” T cells, bearing a unique canonical T cell antigen receptor (TCR) that is highly enriched in mouse prostate tumors. Through this funding, we have successfully generated TCR transgenic mice expressing this canonical “T-reg” antigen receptor. This TCR transgenic mouse strain provides us with a unique research tool that will allow us to determine the developmental origins, lineage stability, and specificity of the canonical tumor-infiltrating T-reg response.

Furthermore, we have analyzed both helper T cell and T-reg responses to cancer by sequencing TCRs of tumor-infiltrating T cell populations using “next-generation” sequencing technologies. This project is an ongoing collaboration with Dr. Nicholas Socci, Assistant Director of the Computational Biology Center at Memorial Sloan-Kettering Cancer Center. Data from this collaboration has yielded two striking findings: 1.) The TCRs expressed by tumor-infiltrating helper T cells are different than the TCRs expressed by tumor-infiltrating T-regs. This demonstrates that helper T cells and T-regs in the tumor infiltrate recognize different antigens, a finding that has both basic implications, and important implications for emerging therapeutic strategies. 2.) The canonical T-reg response that we have identified in mouse prostate cancer is also highly enriched in mouse melanoma tumors. This suggests that T-regs infiltrating different neoplasms may be responsive to shared antigens that are not specific to each unique tumor. This finding suggests that it may be possible to generate “off-the-shelf” therapies that could be used to modulate T-reg associated with a variety of different cancers.

In general, tumor-associated CD4+ T cells fall into two categories. CD4+ “helper” T cells are thought to recognize antigens that are preferentially expressed by tumor cells, and help coordinate anti-tumor immune responses. On the other hand, CD4+ “regulatory” T cells (Tregs), characterized by their expression of the transcription factor Foxp3, are thought to be antagonistic to helper T cells, suppressing their ability to mount an effective antitumor response. Many emerging strategies for the immunotherapy of human cancer have focused on the induction of cancer regression by modulating or depleting tumor associated Tregs prior to administration of cancer vaccines. The goal of our research is to understand the fundamental nature of endogenous tumor-associated Tregs, with respect to their developmental origins, lineage stability, and specificity. Knowledge gained from these studies will provide insight that is vital to the rational development of cancer therapies that effectively target relevant tumor-associated Treg populations while avoiding catastrophic systemic and tumor-associated side effects.

Previous studies identified a population of Tregs bearing a unique T cell antigen receptor (TCR) that is highly enriched in mouse prostate tumors. A mouse model has been generated that expresses this Treg antigen receptor. This TCR transgenic mouse strain provides us with a unique research tool that allows us to determine the developmental origins, lineage stability, and specificity of the canonical tumor-infiltrating Treg response.

Helper T cell and Treg responses to cancer have also been analyzed by sequencing TCRs of tumor-infiltrating T cell populations using next generation sequencing technologies. This is an ongoing collaboration with Dr. Nicholas Socci, Assistant Director of the Computational Biology Center at Memorial Sloan-Kettering Cancer Center. Data collected from this project has resulted in some very interesting results thus far. The TCRs expressed by tumor-infiltrating helper T cells are different than the TCRs expressed by tumor-infiltrating Tregs. This demonstrates that helper T cells and Tregs in the tumor infiltrate recognize different antigens, a finding that has both basic implications, and important implications for emerging therapeutic strategies. Furthermore, the canonical Treg response that we identified in mouse prostate cancer is also highly enriched in mouse melanoma tumors. This suggests that Tregs infiltrating different neoplasms may be responsive to shared antigens that are not specific to each unique tumor. This finding suggests that it may be possible to generate “off-the-shelf” therapies that could be used to modulate Tregs associated with a variety of different cancers.