Recently, we discovered that adoptive transfer of CD39KO tumor-specific (mixed CD4+ and CD8+) T cells, resulted in long-term survival of mice bearing large established tumors. Unexpectedly, we found that these T cells promoted killing of antigen-loss-variants (ALVs) in vivo and prevented tumor recurrence. Moreover, transfer of CD39KO, but not control KO, tumor-specific T cells eradicated large chimeric tumors that contained 10% of ALVs and resulted in long-term tumor-free survival and protection against rechallenge with ALV tumor cells. Based on these novel findings, we hypothesize that transfer of tumor-specific CD39KO T cells will eradicate large established tumors and prevent recurrence of ALV tumors, due to their ability to directly kill the tumor cells and induce anti-ALV responses.
Aim 1 will determine the contribution of type I IFN production at the tumor site in preventing recurrence of ALV tumors.
Aim 2 will determine the role of CD39KO T cells in the recruitment of inflammatory myeloid cells and the induction of type I IFN production for tumor clearance.
Aim 3 will determine whether human tumor-specific CD39KO T cells are also endowed with these abilities to effectively eradicate human tumors in humanized mice. These innovative and mechanistic studies will shed light on the mechanisms underlying CD39KO T cell-mediated antitumor immunity and will thus establish a foundation for translating this discovery into more effective immunotherapies using tumor-specific T-cell subsets in human cancers.
In this project we will determine the roles of specialized white blood cells, called tumor-specific T cells, in promoting an immune response against tumors in mice and determine their potential for use in cancer immunotherapy. We hypothesize that transfer of modified tumor-specific T cells will eradicate large established tumors and prevent recurrence of antigen-loss-variant tumors, due to their ability to 1) directly kill the tumor cells; 2) induce intratumor release of type I IFNs to promote host antitumor immune responses; and 3) effectively eradicate large established tumors in vivo in both mouse and human.
