The Features of Checkpoint Receptor-Ligand Interaction in Cancer and the Therapeutic Effectiveness of Their
Anna Kuzevanova1, Natalya Apanovich1, Danzan Mansorunov1
1Research Centre for Medical Genetics, 1 Moskvorechye St., 115522 Moscow, Russia.
Abstract:
To date, certain problems have been identified in cancer immunotherapy using the inhibition of immune checkpoints (ICs). Despite the excellent effect of cancer therapy in some cases when blocking the PD-L1 (programmed death-ligand 1) ligand and the immune cell receptors PD-1 (programmed cell death protein 1) and CTLA4 (cytotoxic T-lymphocyte-associated protein 4) with antibodies, the proportion of patients responding to such therapy is still far from desirable. This situation has stimulated the exploration of additional receptors and ligands as targets for immunotherapy. In our article, based on the analysis of the available data, the TIM-3 (T-cell immunoglobulin and mucin domain-3), LAG-3 (lymphocyte-activation gene 3), TIGIT (T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains), VISTA (V-domain Ig suppressor of T-cell activation), and BTLA (B- and T-lymphocyte attenuator) receptors and their ligands are comprehensively considered. Data on the relationship between receptor expression and the clinical characteristics of tumors are presented and are analyzed together with the results of preclinical and clinical studies on the therapeutic efficacy of their blocking. Such a comprehensive analysis makes it possible to assess the prospects of receptors of this series as targets for anticancer therapy. The expression of the LAG-3 receptor shows the most unambiguous relationship with the clinical characteristics of cancer. Its inhibition is the most effective of the analyzed series in terms of the antitumor response. The expression of TIGIT and BTLA correlates well with clinical characteristics and demonstrates antitumor efficacy in preclinical and clinical studies, which indicates their high promise as targets for anticancer therapy. At the same time, the relationship of VISTA and TIM-3 expression with the clinical characteristics of the tumor is contradictory, and the results on the antitumor effectiveness of their inhibition are inconsistent.
Insights
New cancer immunotherapies targeting immune checkpoints like PD-L1, PD-1, and CTLA4 show promise. This study analyzes TIM-3, LAG-3, TIGIT, VISTA, and BTLA receptors for improved cancer treatment strategies.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Current cancer immunotherapies targeting PD-L1, PD-1, and CTLA4 have limitations in patient response rates.
- The need for novel immune checkpoint targets is crucial for advancing cancer treatment.
- Exploration of alternative immune checkpoints is essential for improving therapeutic efficacy.
Purpose of the Study:
- To comprehensively review and analyze T-cell immunoglobulin and mucin domain-3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT), V-domain Ig suppressor of T-cell activation (VISTA), and B- and T-lymphocyte attenuator (BTLA) receptors as potential immunotherapy targets.
- To evaluate the relationship between the expression of these immune checkpoints and tumor clinical characteristics.
- To assess the therapeutic efficacy of blocking these receptors in preclinical and clinical studies.
Main Methods:
- Systematic literature review and data analysis of existing preclinical and clinical studies.
- Analysis of receptor expression patterns in relation to tumor characteristics.
- Evaluation of the efficacy of blocking agents targeting TIM-3, LAG-3, TIGIT, VISTA, and BTLA.
Main Results:
- Lymphocyte-activation gene 3 (LAG-3) inhibition demonstrated the most consistent and effective antitumor response among the analyzed targets.
- T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) and B- and T-lymphocyte attenuator (BTLA) showed promising correlations with clinical characteristics and antitumor efficacy.
- V-domain Ig suppressor of T-cell activation (VISTA) and T-cell immunoglobulin and mucin domain-3 (TIM-3) exhibited contradictory expression patterns and inconsistent therapeutic outcomes.
Conclusions:
- LAG-3, TIGIT, and BTLA represent promising targets for next-generation cancer immunotherapies.
- Further research into VISTA and TIM-3 may be warranted, but their clinical utility requires further clarification due to inconsistent findings.
- Targeting novel immune checkpoints beyond PD-1/PD-L1 and CTLA4 holds significant potential for improving patient outcomes in cancer treatment.
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