Regarded as the first step of antitumoral response and a critical component of adaptive immunity, antigen procession and presentation are essential for long-lasting immune surveillance. It enables the adaptive immune system to detect and identify pathogens and mutations, ensuring the initiation of adaptive immune responses against invading microorganisms. Accordingly, enhancing antigen procession and presentation is one of the directions for coping with ICB resistance, through strategies including oncolytic viruses, cancer vaccines, chemotherapy, radiotherapy, and targeted therapy.
Fig.1 Antigen procession and presentation machinery in tumor cells.1
Oncolytic viruses (OVs) are organisms that can identify, infect, and lyse cells in the tumor environment and are considered to have potential as cancer therapeutics. OVs release tumor-associated antigens, danger-associated molecular patterns (DAMPs), and pathogen-associated molecular patterns (PAMPs), thus promoting the development and function of antigen-presenting cells (APCs). Besides, OVs can also activate the immune system by forming a pro-inflammatory environment to promote T cell recruitment and tumor infiltration. Based on the mechanisms, there have been many studies on combination therapeutic regimens of OVs and ICBs during the past years. In a preclinical study in 2014, OV therapy was reported to increase tumor-specific CD4+ and CD8+ T cell infiltration to improve the therapeutic efficacy of CTLA-4 blockade, while another study in 2018 demonstrated that OV therapy increased the sensitivity of triple-negative breast cancer to ICBs and prevent tumor relapse. Several clinical trials have been ongoing to assess the efficacy of combination therapies involved with OVs and ICBs, including NCT02263508, NCT01740297, NCT03206073, and NCT02965716.
Cancer vaccines, including various types such as viral component vaccines, synthetic peptide vaccines, DNA/RNA vaccines, and conjugate vaccines, are used for preventing the development of cancer and reducing risk, or used as therapeutic cancer vaccines or tumor antigen vaccines in treatment for existing cancer. Especially, neo-antigens encoded by somatic mutation in individual cancer based on the loss of expression in healthy tissues, have been recognized as promising vaccine targets.
Cancer vaccines can induce broad immune responses by directly enhancing immunogenicity and stimulating effector immune cells. Previous studies revealed that increased tumor immunogenicity can switch "cold" tumors into "hot" ones and induce PD-L1 expression in TME, leading to enhanced sensitivity of tumors to PD-1/PD-L1 blockades. It was also demonstrated that neo-antigen vaccines significantly induced multi-functional effector T cell responses, and recurrence was not observed in 4 of 6 patients with melanoma after 25 months of treatment with neo-antigen vaccines. Clinical trials including NCT03532217, NCT03289962, and NCT04072900 are underway to evaluate neo-antigen vaccines and ICBs combinatory regimens.
Although the disadvantages of producing systemic immunosuppressive effects are widely known, chemotherapeutic agents can promote antigen presentation by up-regulating the expression of tumor antigens, thereby creating a comfortable immune environment. It was reported by previous clinical trials that a combination of mAbs and platinum-based chemotherapy enhanced antitumor response, and significantly improved PFS (8.8 versus 4.9 months) and overall survival at 12 months in patients with advanced NSCLC. There are also clinical trials on combinatory regimens of chemotherapy along with CTLA-4 blockade (NCT03215706 and NCT02659059), PD-1 blockade (NCT03904537 and NCT02961101), and PD-L1 blockade (NCT03456063 and NCT03164993).
Much evidence has been discovered during these years, showing that combinatory therapies of radiotherapy and ICBs exhibit better efficacy than ICB monotherapy in various cancers. Radiotherapy is reported to upregulate the expression of PD-L1 on tumor cells, making tumors sensitive to anti-PD-1/PD-L1 therapy. Moreover, radiotherapy associated with ICB destroys the immune-inhibitory environment and increases the diversity of TCR repertoire of TILs. A number of clinical trials are being held to evaluate the efficiency and safety of radiotherapy in combination with ICBs in different types of cancers, such as NCT03898895, NCT03480334, and NCT04017897.
Target therapy aims to recognize and attack certain types of cancer cells precisely. Researchers have identified numerous signaling pathways that regulate the progression of malignant tumors during the past decade, antibodies and inhibitors targeting these pathways, and corresponding targeted therapies have also emerged. Sufficient data has proved that targeted therapy could enhance the recognition and effector function of T cells and relieve the immunosuppressive environment, exhibiting anticancer effects in combination with immunotherapy, especially ICBs.
In a phase 1 trial NCT02130466, BRAF inhibitor, MEK inhibitor, and PD-1 blockade combination therapy led to long-lasting responses with controllable toxicity in patients with BRAF-mutant melanoma and increased the expression of MHC class I molecules as well as immune cell infiltration. Targeted agents against MAPK, PI3K-AKT, and EGFR signaling pathways with ICBs are under investigation and some are undergoing clinical trials, including NCT02858921, NCT02625337, and NCT03149029.
Enhancing antigen procession and presentation is a promising strategy to overcome resistance to immune checkpoint therapy. Based on abundant experience and advanced technology platforms, Creative Biolabs provides professional services related to immune checkpoint to assist you in research, including but not limited to:
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