Paving the Way to Solid Tumors: Challenges and Strategies for Adoptively Transferred Transgenic T Cells in the Tumor Microenvironment

Abstract

T cells are important players in the antitumor immune response. Over the past few years, the adoptive transfer of genetically modified, autologous T cells—specifically redirected toward the tumor by expressing either a T cell receptor (TCR) or a chimeric antigen receptor (CAR)—has been adopted for use in the clinic. At the moment, the therapeutic application of CD19- and, increasingly, BCMA-targeting-engineered CAR-T cells have been approved and have yielded partly impressive results in hematologic malignancies. However, employing transgenic T cells for the treatment of solid tumors remains more troublesome, and numerous hurdles within the highly immunosuppressive tumor microenvironment (TME) need to be overcome to achieve tumor control. In this review, we focused on the challenges that these therapies must face on three different levels: infiltrating the tumor, exerting efficient antitumor activity, and overcoming T cell exhaustion and dysfunction. We aimed to discuss different options to pave the way for potent transgenic T cell-mediated tumor rejection by engineering either the TME or the transgenic T cell itself, which responds to the environment.

Reprogramming of Treg cells in the inflammatory microenvironment during immunotherapy: a literature review

“…A phase I clinical study showed that docetaxel can increase CTL in colorectal cancer patients while simultaneously reducing CD25+CD4+ T cells, thereby enhancing the body’s antiviral response. On the other hand, vincristine can inhibit the proliferation of IL-10 secreting Tregs ex vivo, while upregulating antigen-specific CTL ( 75 , 76 ). Thalidomide and its derivatives can be used to treat multiple myeloma ( 77 ).…”

Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness

“… 25 , 26 However, the tumor microenvironment (TME) can limit T cell antitumor efficacy by impacting various fitness traits, including survival, proliferation, and functional persistence. 27 , 28 , 29 This can be driven by distinct stimulation contexts, resulting in cell differentiation into several states. For example, different intensity and duration of stimulation determine whether, and to what extent, T cells can exert their effector functions.…”

Combination of CAR‑T cell therapy and radiotherapy: Opportunities and challenges in solid tumors (Review)

“…Moreover, when CARs are added to T-cells, they can be designed to specifically recognize and bind to these proteins or gangliosides on the surface of cancer cells (8). This recognition triggers the activation of the T-cells and leads to the destruction of the cancer cells; to date, four generations of CARs have been created (9). The first-generation CARs only possess an intracellular signaling domain of CD3ξ to activate T cells (10).…”