Engineering T cells to survive and thrive in the hostile tumor microenvironment

Chimeric antigen receptor–T-cell therapy has demonstrated unprecedented remission rates in patients suffering from relapsed and refractory acute lymphoblastic leukemia, non-Hodgkin's lymphoma, and refractory multiple myeloma. However, objective responses to adoptive T-cell therapy remain suboptimal in patients with solid tumors. A major obstacle for adoptive T-cell therapy for solid tumors is the intrinsic ability of tumors to evolve and to develop mechanisms that inhibit the immune system's innate ability to recognize and kill the tumor cells. This review delineates some of the major immunosuppressive barriers within the tumor microenvironment (TME) that ultimately neutralize the antitumor function of adoptively transferred T cells. Recent advances in engineering strategies have been applied to T cells to survive and overcome the hostile TME.