Biomarkers for immune checkpoint inhibition in sarcomas – are we close to clinical implementation?

Abstract

Sarcomas are a group of diverse and complex cancers of mesenchymal origin that remains poorly understood. Recent developments in cancer immunotherapy have demonstrated a potential for better outcomes with immune checkpoint inhibition in some sarcomas compared to conventional chemotherapy. Immune checkpoint inhibitors (ICIs) are key agents in cancer immunotherapy, demonstrating improved outcomes in many tumor types. However, most patients with sarcoma do not benefit from treatment, highlighting the need for identification and development of predictive biomarkers for response to ICIs. In this review, we first discuss United States (US) Food and Drug Administration (FDA)-approved and European Medicines Agency (EMA)-approved biomarkers, as well as the limitations of their use in sarcomas. We then review eight potential predictive biomarkers and rationalize their utility in sarcomas. These include gene expression signatures (GES), circulating neutrophil-to-lymphocyte ratio (NLR), indoleamine 2,3-dioxygenase (IDO), lymphocyte activation gene 3 (LAG-3), T cell immunoglobin and mucin domain-containing protein 3 (TIM-3), TP53 mutation status, B cells, and tertiary lymphoid structures (TLS). Finally, we discuss the potential for TLS as both a predictive and prognostic biomarker for ICI response in sarcomas to be implemented in the clinic.

Immune pathway through endometriosis to ovarian cancer

“…Another important molecule for the immunomodulator properties of ovarian cancer microenvironment is T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), associated with higher IL-10 production and inhibition of T cell action in multiple tumors[ 158 ]. Currently, it is being tested in preclinical settings as a possible target for monoclonal antibodies in cancer treatment in association with PD-1/PD-L1 inhibitors[ 159 , 160 ].…”

The importance of protein domain mutations in cancer therapy

“…Nevertheless, not all patients respond equally to immunotherapy, so biomarkers that can predict treatment response and guide treatment decisions are required. Many studies have found protein domain alterations linked to immunotherapy response, including mutations in kinase domain at V617F of JAK1/2 , DNA-binding domain of TP53 at L22Q, W23S influencing the genes immune checkpoint inhibition (ICI) including PD-1 , PD-L1 and CTLA-4 [ [153] , [154] , [155] ]. However, predicting individual responses remains intricate, demanding a comprehensive approach considering multiple biomarkers and the intricate dynamics of the tumor microenvironment.…”

Perioperative immunotherapy for esophageal squamous cell carcinoma

“…This reflects the compelling need of unveiling novel targets for immunotherapy that allow to expand the spectrum of ICB-based strategies to achieve optimal therapeutic efficacy and benefit for cancer patients ( 7 ). New immune checkpoint inhibitors that mediate T cell inhibitory signaling such as lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin domain-3 (TIM-3), V-domain Ig suppressor of T cell activation (VISTA), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), inducible T-cell co-stimulatory receptor (ICOS), Nuclear receptor subfamily 2, group F, member 6 (NR2F6), sialic acid-binding immunoglobulin-like lectins-8 (SIGLEC8) and B and T lymphocyte attenuator (BTLA) are developed to overcome resistance to cancer immunotherapy and improve the outcome for cancer patients ( 8 – 10 ). Some of these new drugs and therapeutic regimens have been tested in clinical studies and achieved promising results.…”