Clinical Response to Anti-CD47 Immunotherapy Is Associated with Rapid Reduction of Exhausted Bystander CD4+ BTLA+ T Cells in Tumor Microenvironment of Mycosis Fungoides

Abstract

Cancer progression in mycosis fungoides, the most common form of cutaneous T-cell lymphoma, occurs in a predictable, sequential pattern that starts from patches and that evolves to plaques and later to tumors. Therefore, unlocking the relationship between the microarchitecture of mycosis fungoides and the clinical counterparts of that microstructure represents important steps for the design of targeted therapies. Using multispectral fluorescent imaging, we show that the progression of mycosis fungoides from plaque to tumor parallels the cutaneous expansion of the malignant CD4+ T cells that express TOX. The density of exhausted BTLA+ CD4+ T cells around malignant CD4+TOX+ cells was higher in tumors than it was in plaques, suggesting that undesired safeguards are in place within the tumor microenvironment that prevent immune activation and subsequent cancer eradication. Overriding the CD47 checkpoint with an intralesional SIRPαFc fusion decoy receptor induced the resolution of mycosis fungoides in patients that paralleled an amplified expansion of NK and CD8+ T cells in addition to a reduction of the exhausted BTLA+ CD4+ T cells that were engaged in promiscuous intercellular interactions. These therapeutic benefits of the CD47 blockade were further unleashed by adjuvant interferon-α, which stimulates cytotoxic cells, underscoring the importance of an inflamed microenvironment in facilitating the response to immunotherapy. Collectively, these findings support CD47 as a therapeutic target in treating mycosis fungoides and demonstrate a synergistic role of interferon-α in exploiting these clinical benefits.

TOX Expression in Mycosis Fungoides and Sezary Syndrome

“…Furthermore, Morimura et al [44] described an increase of the marker levels as the disease progressed, a finding also observed in our cases. Indeed, in our analysis, the increase in TOX expression in advance-phase disease as well as the higher TOX expression in A+ and DOD patients when compared to A− ones corroborate the hypothesis that TOX may be regarded more as a prognostic than as a diagnostic marker [6,8,51,52]. Such evidence may be emphasized by the decrease in TOX levels in two patients (no 14 and 18) who had a relapse in early-stage patch after TSEBI+bexarotene treatment with a decreased expression in TOX levels.…”

Sustained high expression of BTLA on CD4+ T cell contributes to high rate of bacterial infection and mortality in patients with HBV-related acute-on-chronic liver failure via CD4+ T cell exhaustion

“…To further explore the proliferation and functional characteristics of BTLA + CD4 + T cells, we sorted BTLA + CD4 + T cells and BTLA − CD4 + T cells from NC by ow cytometry and found that compared with BTLA − CD4 + T cells, BTLA + CD4 + T cells secreted higher levels of IFN-γ, IL-2, and TNF-α, and had higher proliferation ability, which was similar to a previous study 23 . (Fig.…”

“…Recent studies indicate that exhaustion of CD4 + T cells caused by coinhibitory signals (such as PD-1, CTLA-4, and BTLA) and a lack of CD4 + T cells contributes to CD8 + T cell immune dysfunction. 23,32 Therefore, it is not di cult to speculate that the elevated levels of BTLA in CD4 + T cells will eventually lead to CD8 + T cell immune disorder.…”

CD47‐SIRPα blocking‐based immunotherapy: Current and prospective therapeutic strategies

“… 83 , 99 Moreover, in cutaneous T‐cell lymphoma, treatment with intratumoural rhSIRPα injections triggered expansion of NK and CD8+ T cells in the TME. 100 Similarly, in mice xenografted with DLD1‐cOVA‐RFP+ cancer cells and treated with CD47 blocking mAb, the popliteal lymph nodes contained more proliferating OT‐I T cells in comparison to IgG treatment. Moreover, these macrophages primed an antitumour CD8+ T‐cell response in vivo that protected mice from rechallenge with the same cancer cell line.…”

“…The efficacy of CD47 blocking in several mouse models relied on T‐cell and NK‐cell responses, with knockout of these cells negating therapeutic activity 83,99 . Moreover, in cutaneous T‐cell lymphoma, treatment with intratumoural rhSIRPα injections triggered expansion of NK and CD8+ T cells in the TME 100 . Similarly, in mice xenografted with DLD1‐cOVA‐RFP+ cancer cells and treated with CD47 blocking mAb, the popliteal lymph nodes contained more proliferating OT‐I T cells in comparison to IgG treatment.…”