MYC 网络与弥漫大 B 细胞淋巴瘤中 CD8 T 细胞存在减少相关，并可能通过 AZD4573 与 Selinexor 的协同联合加以干预——一项初步分析

Diffuse Large B-cell Lymphoma (DLBCL) is a genomically-heterogenous disease affecting over 70,000 patients per year that presents a clinical challenge despite the success of frontline regimens and second-line Chimeric Antigen receptor T-cell (CAR-T) therapy. Recently, genomic alterations and tumor microenvironment features associated with poor CAR-T response have been identified, with MYC amplification emerging in new analyses. This retrospective analysis aimed to integrate various data to identify genomic partnerships capable of providing added clarity and actionable treatment targets within this population. Publicly-available data were analyzed for differential expression based on MYC, 24-month event-free survival (EFS24) status, and CAR-T response. Notable T-cell partner genes such as IL7R (FDR = 0.

00150) and CD58 (FDR = 5. 375E-06) and cell death mediators such as PDCD1LG2 (FDR = 4. 061E-06) were significantly lost in patients with High/Altered MYC that also failed EFS24. CD8 T-cell presence was also significantly lower in High/Altered MYC de-novo patients (p = 0. 00112) and CAR-T non-responders (p = 0. 00835).

De-novo patients with both High/Altered MYC and CD8 T-cell absence faced a significantly inferior survival compared to counterparts with only one factor or neither (p = 0. 0226). rrDLBCL patients reflected similar oncogenic pathways associated with greater scRNA MYC expression. In vitro application of the CDK9 inhibitor AZD4573 and XPO1 inhibitor Selinexor significantly reduced DLBCL cell line viability as single agents and produced synergistic results when applied in combination.

Our analysis presents key associations between the MYC oncogene and depleted TME presence capable of providing clarity within the evolving precision CAR-T treatment landscape.