Negative intracellular regulators of T-cell receptor (TCR) signaling as potential antitumor immunotherapy targets

Abstract

Immunotherapy strategies aim to mobilize immune defenses against tumor cells by targeting mainly T cells. Co‐inhibitory receptors or immune checkpoints (ICPs) (such as PD-1 and CTLA4) can limit T cell receptor (TCR) signal propagation in T cells. Antibody-based blocking of immune checkpoints (immune checkpoint inhibitors, ICIs) enable escape from ICP inhibition of TCR signaling. ICI therapies have significantly impacted the prognosis and survival of patients with cancer. However, many patients remain refractory to these treatments. Thus, alternative approaches for cancer immunotherapy are needed. In addition to membrane‐associated inhibitory molecules, a growing number of intracellular molecules may also serve to downregulate signaling cascades triggered by TCR engagement. These molecules are known as intracellular immune checkpoints (iICPs). Blocking the expression or the activity of these intracellular negative signaling molecules is a novel field of action to boost T cell-mediated antitumor responses. This area is rapidly expanding. Indeed, more than 30 different potential iICPs have been identified. Over the past 5 years, several phase I/II clinical trials targeting iICPs in T cells have been registered. In this study, we summarize recent preclinical and clinical data demonstrating that immunotherapies targeting T cell iICPs can mediate regression of solid tumors including (membrane associated) immune‐checkpoint inhibitor refractory cancers. Finally, we discuss how these iICPs are targeted and controlled. Thereby, iICP inhibition is a promising strategy opening new avenues for future cancer immunotherapy treatments.

Serum cell division cycle 42 reflects the treatment response and survival in patients with advanced cervical cancer who receive immune checkpoint inhibitor treatment

“…The present study revealed that serum CDC42 at baseline was not significantly decreased in patients with objective response achievement and disease control achievement; PFS and OS after ICI treatment in patients with advanced cervical cancer were decreased in patients with baseline CDC42 ≥600 pg/ml. These findings might be because CDC42 negatively modulated the differentiation of CD8 + T cells, which killed tumor cells following suppression of immune escape by ICI treatment (15,32). As aforementioned, CDC42 was associated with larger tumor size, pelvis metastasis and lung metastasis, which represent higher tumor burden.…”

IQGAP3 promotes the progression of glioma as an immune and prognostic marker

“…Additionally, some emerging immune checkpoints are under investigation, such as T cell immunoglobulin and mucin-domain containing-3 (TIM-3), B7 homolog 3 protein (B7-H3), and B7 homolog 4 protein (B7-H4) [ 55 ]. Targeting ICPs (immune checkpoint inhibitors, ICIs) can limit T cell receptor (TCR) signaling [ 56 ]. As a result, ICI therapy has brought significant breakthroughs in cancer immunotherapy for patients [ 57 ].…”

Integrative network analysis of transcriptomics data reveals potential prognostic biomarkers for colorectal cancer

“…Studies have reported the pivotal role of NK and T cell‐mediated cytotoxicity in eliminating cancer cells and its potential in immunotherapy. It is reported that the NK and T cells share some cytotoxic mechanisms, such as the release of perforin and granzymes, which can be effective against cancer cells 35,36 …”