BRAF and MEK inhibition in melanoma patients enables reprogramming of tumor infiltrating lymphocytes

Abstract

Background Combined inhibition of BRAF/MEK is an established therapy for melanoma. In addition to its canonical mode of action, effects of BRAF/MEK inhibitors on antitumor immune responses are emerging. Thus, we investigated the effect of these on adaptive immune responses. Patients, methods and results Sequential tumor biopsies obtained before and during BRAF/MEK inhibitor treatment of four (n = 4) melanoma patients were analyzed. Multiplexed immunofluorescence staining of tumor tissue revealed an increased infiltration of CD4+ and CD8+ T cells upon therapy. Determination of the T-cell receptor repertoire usage demonstrated a therapy induced increase in T-cell clonotype richness and diversity. Application of the Grouping of Lymphocyte Interactions by Paratope Hotspots algorithm revealed a pre-existing immune response against melanoma differentiation and cancer testis antigens that expanded preferentially upon therapy. Indeed, most of the T-cell clonotypes found under BRAF/MEK inhibition were already present in lower numbers before therapy. This expansion appears to be facilitated by induction of T-bet and TCF7 in T cells, two transcription factors required for self-renewal and persistence of CD8+ memory T cells. Conclusions Our results suggest that BRAF/MEK inhibition in melanoma patients allows an increased expansion of pre-existing melanoma-specific T cells by induction of T-bet and TCF7 in these.

Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling

“…Improved antigenspecific T cell function has been associated with antigen clearance in humans with hepatitis C infection treated with direct-acting antiviral therapies (62)(63)(64)(65)(66). Similarly, an immunomodulatory effect of dasatinib on T cells has been associated with improved antitumor immunity (67,68), and BRAF and MEK inhibition in patients with melanoma leads to up-regulation of TCF7 and expansion of melanoma-specific tumor-infiltrating lymphocyte (TIL) (69). Collectively, these observations suggest that the transient cessation of TCR signaling could provide a widely applicable but underappreciated approach to enhance functionality in populations of exhausted human T cells; however, additional studies are needed to more fully define the effects of rest on nonengineered, exhausted T cells.…”

Tumor Infiltrating Lymphocyte (TIL) Therapy for Solid Tumor Treatment: Progressions and Challenges

“…However, the clinical response of BRAF inhibitors is usually short-lived [ 108 ], and as the disease progresses, alternative treatments available to patients is limited. Peiffer and colleagues indicated that BRAF/MEK inhibitors can promote the proliferation of melanoma-specific T cells in patients with melanoma [ 109 ]. Recently, in a clinical trial, seven of 11 patients with metastatic melanoma who received a combination treatment of TILs, HD IL-2, and vemurafenib experienced an objective clinical response, two of which achieved a complete response [ 110 ].…”

Changes in the Immune Cell Repertoire for the Treatment of Malignant Melanoma

“…These are essential for central memory and maintenance of more differentiated T cells, respectively. An analysis conducted in melanoma patients showed that T-bet and TCF7 are upregulated by BRAF/MEK inhibition [ 34 ]. The repertoire of T cells found in tumors before treatment is expanded after the administration of BRAF/MEK inhibitors.…”

“…T-bet is important to maintain the balance between T cell memory and effector differentiation pathways and to trigger Th1 responses characterized by the interferon gamma (IFN-γ) signature [ 36 ]. These findings suggest that TCF7 and T-bet induced during BRAF/MEK inhibition promote the repertoire expansion of intratumoral T cells [ 34 ].…”