Tumor stromal barriers to the success of adoptive T cell therapy

Adoptive transfer of tumor competent T cells has long been studied as a therapeutic modality that may result in complete tumor eradication [1]. Indeed, T cells have the potential to home to all sites of metastatic disease no matter where the location and induce antigen-speciWc cell destruction. Theoretically, local clonal expansion of T cells in response to antigen will allow persistent killing over time until every cancer cell has been eradicated. No chemotherapeutic or biologic therapy developed to date has the ability to result in a persistent long lived anti-tumor eVect. Unfortunately, the road to developing successful adoptive T cell therapy as a standard treatment for solid tumors has been littered with roadblocks. Barriers to success have included diYculty in expanding T cells ex vivo to the number needed to elicit an anti-tumor eVect, a need to better deWne the speciWc eVector populations mediating tumor regression, and a lack of consensus as to the appropriate origin of the T cells to be used for expansion, i.e. derived from tumor, lymph nodes, or peripheral blood, to name a few [2]. Moreover, the development of T regulatory cells (Treg) [3], co-expanded ex vivo with activated T cells, can dampen the function of tumor-speciWc T cells and prevent eVective in vivo expansion, thereby limiting anti-tumor responses [4]. Investigations have also focused on the optimization of the eVector T cell to enhance tumor homing and clinical eYcacy [5–7]. In this issue of Cancer Immunology and Immunotherapy, however, Bernhard et al. [8] elegantly demonstrate that functional eVectors, capable of homing to antigen, encounter further barriers at the site of the tumor. A detailed analysis of an infused HER-2/neu speciWc CD8 T cell clone, in a patient with breast cancer, suggests that tumor stromal factors [9] may be preventing egress of T cells into malignant parenchyma. Following ex vivo expansion and infusion into patients, T cells must retain anti-tumor activity, survive and persist, and localize to all tumor sites [10]. T cells that lack these properties are destined to have limited anti-tumor eYcacy in vivo. EVorts to improve anti-tumor activity by optimizing speciWcity include the introduction of deWned T cell receptor chains or chimeric antigen receptors to generate high-avidity tumor-reactive T cells [7]. Delivery of survival signals can be mediated via restoration of costimulatory signals and co-administration of growth cytokines, such as IL-2 [5]. Furthermore, T cell homing to tumors can be improved through use of tissue-speciWc chemokine receptors, such as CCL21 [11]. Despite optimizing the T cell product, it is clear that failure can occur due to the tumor microenvironment. Cancer immunoediting can arise, i.e. the host’s immune system can facilitate outgrowth of tumor cell variants that downregulate or lose antigen [12] and MHC class I and II, thereby decreasing the immunogenicity of the tumor [13]. Therefore, while an adaptive immune response can be induced by antigen-speciWc T cells, cancer immune surveillance is often inadequate at controlling carcinogenesis and disease progression. Furthermore, within the tumor microenvironment, tumor-derived and Tregderived cytokines, such as IL-10 and TGF, can facilitate Commentary on “Adoptive transfer of autologous, HER2-speciWc, cytotoxic T lymphocytes for the treatment of HER2-overexpressing breast cancer” by Helga Bernhard et al.