OBJECTIVE
Systemic sclerosis (SSc) is characterized by immune dysregulation and fibrosis. We investigated whether abatacept modulates CD319/SLAMF7-expressing cytotoxic T cells implicated in diffuse cutaneous SSc.
METHODS
In this ancillary ASSET trial analysis, PBMCs from 67 participants were analyzed at baseline and months 1, 3, and 6. Flow cytometry quantified CD4+CD319+ and CD8+CD319+ T cells, cytotoxic/activation markers, and stimulated intracellular IL-4, IL-17A, and IFN-γ. Analyses compared abatacept-treated molecular endotypes with placebo and related immune changes to modified Rodnan skin score (mRSS) change. Skin single-cell RNA sequencing included 5 healthy controls and 8 SSc patients.
RESULTS
At baseline, CD319+ T cells showed greater cytokine production, activation, and granzyme/perforin expression than CD319- T cells in 60 evaluable participants (p<0.001 to p<0.0001). Abatacept reduced CD4+CD319+ and CD8+CD319+ T cell frequencies at month 6; placebo did not. Effects were strongest in fibroproliferative patients, where CD8+CD319+ T cells decreased versus placebo (n=7 versus n=36; p=0.0377). In this endotype, abatacept reduced IL-4 in CD4+CD319+ and CD8+CD319+ T cells at month 3 (p=0.0468 and p=0.0287) and IL-17A in CD8+CD319+ T cells at month 6 (p=0.0004), while IFN-γ was unchanged. Reduction in CD4+CD319+ T cells correlated with mRSS improvement in abatacept-treated patients (r=0.5297, p=0.0423). Skin single-cell RNA-sequencing showed increased SLAMF7 expression in SSc T cells (p=0.017), enriched within cytotoxic subsets.
CONCLUSION
CD319+ T cells represent highly differentiated, activated cytotoxic effector populations in SSc. Abatacept selectively modulates these cells and suppresses associated pro-fibrotic and pro-inflammatory cytokines, particularly in the fibroproliferative subtype, where CD319+ T cell reductions correlate with clinical improvement.
Mikel Gurrea-Rubio, Laura A. Cooney, Kohei Maeda et al.· Arthritis & Rheumatology· 0 citations
Melanoma is responsible for 80% of skin cancer-related deaths. Approximately 50% of melanoma patients carry the BRAFV600E mutation, which promotes tumor growth. While the use of BRAF inhibitors (BRAFi) has improved outcomes, acquired resistance is a persistent clinical challenge and the impact of BRAFi resistance on the immune tumor microenvironment (iTME) is incompletely understood. We have shown that the addition of the synthetic triterpenoid CDDO-Me to the BRAFi PLX4720 arrested resistance and significantly reduced tumor burden, while CDDO-Me as a single agent or in combination with BRAFi prior to resistance was ineffective. Thus, we hypothesize that this disparity in treatment efficacy may be attributable to temporally regulated BRAFi treatment-induced changes to the iTME.
Drug-induced changes in the iTME pre and post-resistance were characterized in tumors of engrafted transgenic BRAF/Pten mice using scRNA-seq, flow cytometry, and ELISA. T cell proliferation assays were used to assess functional changes in tumor-conditioned myeloid cells.
BRAFi treatment attenuated immunosuppressive myeloid activation pre-resistance, while BRAFi resistance was associated with enhanced tumor-associated macrophage (TAM) recruitment and immunosuppressive myeloid subset activation. However, the addition of CDDO-Me to BRAFi at resistance reversed these outcomes and rescued the ability of TAMs to induce T cell proliferation.
The iTME changes with tumor progression and responds dynamically to BRAFi treatment and resistance. This work establishes for the first time that BRAFi promotes myeloid-mediated induction of T cell activation, which is lost at resistance but can be rescued with the addition of CDDO-Me. Because BRAFi resistance and iTME immunosuppression is reversed by CDDO-Me treatment, these results provide the foundation for its potential use in combination therapies for melanoma.
Dartmouth Health Cancer Center Developmental Funding (Prouty Pilot Grant)
Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
Chen-Yu Wang, G. Torres, Helen C. Jarnagin et al.· Journal of Immunology· 0 citations