Advances in therapeutic targeting of immune checkpoints receptors within the CD96-TIGIT axis: clinical implications and future perspectives

ABSTRACT

Introduction

The development of therapeutic antibodies targeting immune checkpoint molecules (ICMs) that induce long-term remissions in cancer patients has revolutionized cancer immunotherapy. However, a major drawback is that relapse after an initial response may be attributed to innate and acquired resistance. Additionally, these treatments are not beneficial to all patients. Therefore, the discovery and targeting of novel ICMs and their combination with other immunotherapeutics are urgently needed.

Areas covered

There has been increasing evidence of the CD96-TIGIT axis as ICMs in cancer immunotherapy in the last five years. This review will highlight and discuss the current knowledge about the role of CD96 and TIGIT in hematological and solid tumor immunotherapy in the context of empirical studies and clinical trials, and provide a comprehensive list of ongoing cancer clinical trials on the blockade of these ICMs, as well as the rationale behind combinational therapies with anti-PD-1/PD-L1 agents, chemotherapy drugs, and radiotherapy. Moreover, we share our perspectives on anti-CD96/TIGIT-related combination therapies.

Expert opinion

CD96-TIGIT axis regulates anti-tumor immune responses. Thus, the receptors within this axis are the potential candidates for cancer immunotherapy. Combining the inhibition of CD96-TIGIT with anti-PD-1/PD-L1 mAbs and chemotherapy drugs has shown relatively effective results in the context of preclinical studies and tumor models.

KEYWORDS:

• Cancer immunotherapy
• DNAM-1
• CD96
• immune checkpoint
• TACTILE
• TIGIT

Article highlights

• CD96-TIGIT axis regulates anti-tumor immune responses.

• The receptors within CD96-TIGIT axis are the potential targets for hematological and solid tumors immunotherapy.

• CD96-TIGIT axis may be a biomarker for determining patient prognosis and immune infiltration in various cancers.

• Combining the inhibition of CD96-TIGIT with other immune checkpoints blockade and chemotherapy drugs has shown relatively effective results in the context of preclinical studies and tumor models.

Abbreviations

ALL: Acute lymphocytic leukemia; AML: Acute myeloid leukemia; APC: Antigen-presenting cell; BiKE: Bispecific killer-cell engager; BiTE: Bispecific T cell engagers; BM: Bone marrow; BsAb: Bispecific antibody; BTLA-4: B and T lymphocyte attenuator; CAR: Chimeric antigen receptor; CLL: Chronic lymphocytic leukemia; CML: Chronic myeloid leukemia; CSC: Cancer stem cell; CTLA-4: Cytotoxic T-lymphocyte-associated protein-4; CTL: Cytotoxic T lymphocyte; DNAM-1: DNAX accessory molecule-1; EGFR: Epidermal growth factor receptor; Eomes: Eomesodermin; FDA: Food and Drug Administration; HCC: Hepatocellular carcinoma; HDAC: Histone deacetylase; HIF: Hypoxia-inducible factor; HNSCC: Head and neck squamous cell carcinomas; ICB: Immune checkpoint blockade; Ig: Immunoglobulin; ICI: Immune checkpoint inhibitor; ICM: Immune checkpoint molecule; irAEs: Immune-related adverse effects; LAG-3: Lymphocyte-activation gene 3; mAb: Monoclonal antibody; MDS: Myelodysplastic syndromes; MM: Multiple myeloma; NP: Nanoparticle; PD-1: Programmed cell death protein-1; VISTA: V-domain Ig suppressor of T cell activation; TACTILE: T cell activation, increased late expression; TCGA: The Cancer Genome Atlas; TIM-3: T cell immunoglobulin and mucin domain-containing protein 3; TIGIT: T cell immunoglobulin and ITIM domain; TIL: Tumor-infiltrating lymphocyte; TME: Tumor microenvironment; TNBC: Triple-negative breast cancer; PBMC: Peripheral blood mononuclear cell; PVR: Poliovirus receptor; Treg: Regulatory T cell; TGF-β: Transforming growth factor-β.

Acknowledgments

All figures were created by the Biorender (Biorender.com).

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

P Farhangnia, M Akbarpour, A Delbandi, and N Rezaei conceptualize the study. P Farhangnia drafted and visualized the manuscript. M Akbarpour, M Yazdanifar, A Aref, A Delbandi, and N Rezaei revising the article critically for important intellectual content. A Delbandi and N Rezair supervised the study. All authors read and approved the final manuscript to be published.

Additional information

Funding

This paper was not funded.