Impacting T-cell fitness in multiple myeloma: potential roles for selinexor and XPO1 inhibitors

Abstract

Competent T-cells with sufficient levels of fitness combat cancer formation and progression. In multiple myeloma (MM), T-cell exhaustion is caused by several factors including tumor burden, constant immune activation due to chronic disease, age, nutritional status, and certain MM treatments such as alkylating agents and proteasome inhibitors. Many currently used therapies, including bispecific T-cell engagers, anti-CD38 antibodies, proteasome inhibitors, and CART-cells, directly or indirectly depend on the anti-cancer activity of T-cells. Reduced T-cell fitness not only diminishes immune defenses, increasing patient susceptibility to opportunistic infections, but can impact effectiveness MM therapy effectiveness, bringing into focus sequencing strategies that could modulate T-cell fitness and potentially optimize overall benefit and clinical outcomes. Certain targeted agents used to treat MM, such as selective inhibitors of nuclear export (SINE) compounds, have the potential to mitigate T-cell exhaustion. Herein referred to as XPO1 inhibitors, SINE compounds inhibit the nuclear export protein exportin 1 (XPO1), which leads to nuclear retention and activation of tumor suppressor proteins and downregulation of oncoprotein expression. The XPO1 inhibitors selinexor and eltanexor reduced T-cell exhaustion in cell lines and animal models, suggesting their potential role in revitalizating these key effector cells. Additional clinical studies are needed to understand how T-cell fitness is impacted by diseases and therapeutic factors in MM, to potentially facilitate the optimal use of available treatments that depend on, and impact, T-cell function. This review summarizes the importance of T-cell fitness and the potential to optimize treatment using T-cell engaging therapies with a focus on XPO1 inhibitors.

Bone Marrow Spatial Transcriptomics Reveals a Myeloma Cell Architecture with Dysfunctional T-Cell Distribution, Neutrophil Traps, and Inflammatory Signaling

“…Interestingly, the T cell behavior in humans was not as clear as in our MM mouse model, which may indicate some patient heterogeneity or different disease stages. These spatial results could justify previous data, which shows that the dysfunction of cytotoxic T cells induced by cancer at the tumor site could be accountable for immune evasion and the therapeutic failure of immunotherapies 8,[38][39][40] . On the other hand, we confirmed similar transcriptional changes between mice and humans in pathways involving NETosis and IL-17 signaling, among others.…”

“…The disease is characterized by significant genetic and genomic heterogeneity between patients and within individual patients 2,3 . Several studies have demonstrated the role of the BM microenvironment in the development and progression of MM and treatment resistance [4][5][6][7][8] . Various mechanisms have been implicated in the expansion and growth of malignant PC.…”

“…For example, the release of matrix metalloproteinases (MMPs) facilitates invasion into nearby tissues and metastasis, or the secretion of interleukins promotes myeloma cell growth or inhibits immune function 7,9 . Moreover, the induction of neutrophil extracellular traps (NETs) formation by neutrophils, or the impairment of T cell function, allows tumor expansion 8,10 . All these pieces of evidence suggest that understanding the interplay between malignant cells and their BM microenvironment may contribute to the identification of novel targeted therapies 11,12 .…”