Resistance to Immune Checkpoint Blockade in Uterine Leiomyosarcoma: What Can We Learn from Other Cancer Types?

Abstract

The onset of immune checkpoint blockade (ICB) therapy over the last decade has transformed the therapeutic landscape in oncology. ICB has shown unprecedented clinical activity and durable responses in a variety of difficult-to-treat cancers. However, despite these promising long-term responses, a majority of patients fail to respond to single-agent therapy, demonstrating primary or acquired resistance. Uterine leiomyosarcoma (uLMS) is a rare high-risk gynecological cancer with very limited treatment options. Despite research indicating a strong potential for ICB in uLMS, a clinical trial assessing the response to immunotherapy with single-agent nivolumab in advanced-stage uLMS showed no clinical benefit. Many mechanisms of resistance to ICB have been characterized in a variety of tumor types, and many more continue to be uncovered. However, the mechanisms of resistance to ICB in uLMS remain largely unexplored. By elucidating and targeting mechanisms of resistance, treatments can be tailored to improve clinical outcomes. Therefore, in this review we will explore what is known about the immunosuppressive microenvironment of uLMS, link these data to possible resistance mechanisms extrapolated from other cancer types, and discuss potential therapeutic strategies to overcome resistance.

Status of the Current Treatment Options and Potential Future Targets in Uterine Leiomyosarcoma: A Review

“…A low frequency of TMB-high patients in uLMS was reported [ 35 ]. Furthermore, loss of phosphatase and tensin homolog ( PTEN ), which has a frequency of 17.7% in uLMS [ 36 ], leads to constitutive activation of the phosphatidylinositol-3-kinase/mammalian target of the rapamycin signaling pathway and to an increase in the expression level of vascular endothelial growth factor (VEGF), resulting in resistance to immune checkpoint inhibitors [ 37 , 38 ]. Thus, the therapeutic effect may be improved when used in combination with an inhibitor of treatment-resistant factor, such as anti-VEGF antibody therapies.…”

Resistance to Targeted Agents Used to Treat Paediatric ALK-Positive ALCL

“…Increased AXL receptor tyrosine kinase (AXL) expression Increases regulatory T cells, MDSCs and M2 macrophages [185] Increased Wnt signalling Decreases tumour infiltrating lymphocytes [185] Loss of Phosphatase and tensin homolog (PTEN) Induces vascular endothelial growth factor (VEGF) production and reduces T cell infiltration [176,185] Loss of functional beta 2 microglobulin Dysfunctional CD8 + T cells [175,188] Hypoxia Dysfunctional CD8 + T cells [184,187] Upregulation of T cell immunoglobulin and mucin-domain containing-3 (Tim-3)…”

“…Dysfunctional T helper 1 (Th1) cells and reduced cytokine expression [189,190] Reduced expression of absent in melanoma 2 (AIM2) Decreases inflammation [181] Reduced expression of poliovirus receptor-related immunoglobulin domain containing protein (PVRIG) Dysfunctional CD8 + T cells [181] Increased expression of mannosidase alpha class 2A member 1 (MAN2A1) Altered Th1/T-helper 2 (Th2) axis towards Th2 expression [181] Another cause of resistance to anti-PD-L1 immune checkpoint inhibitors is a reduction in neoantigen expression on the tumour cell surface. A lack of neoantigens, either due to a low tumour mutational burden, or altered antigen processing and presentation, results in a reduced immune response to the tumour, which compensates for the immunosuppressive effects of PD-L1 signalling that have been lost [180,185,191].…”

“…Alternatively, resistance to anti-PD-L1 immune checkpoint inhibitors can occur as a result of a skew in the distribution of immune cells in the tumour microenvironment towards an immunosuppressive one, compensating for the effects of loss of PD-L1 signalling. This skew can be caused by a low overall T cell abundance [ 181 ], an increased ratio of regulatory T cells to effector T cells [ 182 ], dysfunctional CD8 + T lymphocytes [ 183 , 184 ], increased myeloid-derived suppressor cells (MDSCs) [ 185 ] and/or increased PD-L1 positive M2 macrophages [ 185 , 186 ]. These changes are mediated in a variety of ways ( Table 3 ), which might be therapeutically targetable.…”

“…Another cause of resistance to anti-PD-L1 immune checkpoint inhibitors is a reduction in neoantigen expression on the tumour cell surface. A lack of neoantigens, either due to a low tumour mutational burden, or altered antigen processing and presentation, results in a reduced immune response to the tumour, which compensates for the immunosuppressive effects of PD-L1 signalling that have been lost [ 180 , 185 , 191 ].…”