RESUMEN
In many cancers, regulatory T cells (Treg) play a crucial role in suppressing the effector immune response thereby permitting tumor development. Indeed, in mouse models, their depletion can promote the regression of tumors of various origins, including renal cell carcinoma when located subcutaneous (SC). In the present study, we aimed to assess the importance of Treg immunosuppression in the physiologic context of metastatic renal carcinoma (Renca) disease. To that purpose we inoculated renal tumors orthotopically, intra-kidney (IK), in mice. Treg depletions were performed using anti-CD4 antibody in wild type mice or diphtheria toxin (DT) in Foxp3DTR transgenic mice. Our main observation was that Treg were not the key immunosuppressive component of the IK tumoral microenvironment, compared to the same tumors located SC. We demonstrated that the CD8+ effector immune response was still suppressed in IK tumors when compared to SC tumors, following Treg depletion. Furthermore, the level of program cell death protein (PD)-1 was increased on the surface of CD4+ T cells infiltrating IK tumors compared to SC tumors. Finally, the Treg-independent immunosuppression, occurring in IK tumors, was potent enough to inhibit regression of concomitant SC tumors, normally responsive to Treg depletion. Our findings provide further insight into the immunosuppressive nature of the immune response generated in the kidney microenvironment, suggesting that it can have additional mechanisms in addition to Treg. These observations might help to identify better targets from the kidney tumor microenvironment for future cancer therapies.
RESUMEN
Adoptive immunotherapy is a promising approach for the treatment of cancer; however, autoimmunity against normal tissue can be a serious complication of this therapy. We hypothesized that T-cell cultures responding maximally only when engaging two antigens would be more specific for tumor cells, and less active against normal cells, as long as the tumor expressed both antigens, while normal cells expressed only one of the antigens. A model system was developed consisting of cell lines expressing either folate binding protein or erbB-2, representing 'normal' tissue, and cells expressing both antigens representing tumor tissue. Human T-cell cultures were produced using two chimeric antigen receptor vectors ('dual transduced'), or using a single chimeric antigen receptor vector (monospecific). Dual-transduced T cells responded less against 'normal' cells compared with tumor cells. This relatively simple procedure produced T-cell cultures that were as active against a tumor as the monospecific cultures used traditionally, but had lower activity against model normal cells.
Asunto(s)
Inmunoterapia Adoptiva/métodos , Neoplasias/inmunología , Neoplasias/terapia , Receptores de Antígenos de Linfocitos T/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Linfocitos T/inmunología , Animales , Autoinmunidad , Línea Celular Tumoral , Células Cultivadas , Femenino , Glicina N-Metiltransferasa/genética , Glicina N-Metiltransferasa/metabolismo , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Proteínas Recombinantes de Fusión/genética , Transducción GenéticaRESUMEN
IMPORTANCE OF THE FIELD: Conventional therapies, including surgery, chemotherapy and radiotherapy have contributed much to cancer treatment. However, these treatment modalities fail in a large proportion of patients, and there is a great need for effective alternate therapies. Adoptive immunotherapy can be effective against some cancers that have failed all other treatment options, even when disease burdens are massive. AREAS COVERED IN THIS REVIEW: This review gives a brief introduction of the historical origins of adoptive immunotherapy and then provides details of strategies for increasing the potency of cell transfer. Approaches for enhancing adoptive immunotherapy include: selecting the right type of cell; providing cytokine support; preconditioning patients and tuning the tumor microenvironment. The review also provides insights into the safety, feasibility and costs of this form of therapy. WHAT THE READER WILL GAIN: This article will give the reader an appreciation of the potential of adoptive immunotherapy, as well as an understanding of some limitations and current approaches for optimizing the effectiveness of this approach. TAKE HOME MESSAGE: With recent developments in knowledge of the interactions between the immune system and tumors, the field of adoptive immunotherapy is now poised to make dramatic contributions to cancer therapy.
