Immunotherapy with a single drug shows poor efficacy? Group a "CP(Couple)" solve it!

Compared with traditional treatments such as surgery, radiotherapy and chemotherapy, tumor immunotherapy has the advantages of strong specificity and long action time, becoming a very promising research direction in tumor treatment and receiving more and more attention. T-lymphocyte-based tumor immunotherapy has become a powerful tool against cancer, and immune checkpoint inhibitors (ICIs) therapy is one of the most representative tumor immunotherapy methods in clinic. In recent years, significant progress has been made in tumor immunotherapy, especially in the application of immune checkpoint inhibitors. However, due to the heterogeneity of the tumor, only a small number of patients have obtained long-term efficacy, while the majority of the remaining patients have relapsed drug resistance (including primary and acquired resistance). How to solve the unsatisfactory efficacy of immunotherapy with single drug so that more patients can benefit from immunotherapy has become a hot research direction in this field. In this paper, we briefly describe the drug resistance mechanism in immunotherapy and the potential scheme of immunization combined with other treatments to overcome the low response rate in several aspects.

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PART01

Immune checkpoint mechanism of PD-1/PD-L1 immune resistance

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1. The tumor antigen immunogenicity is insufficient

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Tumor cell differ from normal cell in that they are immunogenic due to gene mutations that induce expression of a new series of specific antigenic protein phenotypes. However, heterogeneity is one of the important features of tumors. Significant differences in cell surface antigen expression exist between different types of tumors, or between different subsets within the same tumor, showing different levels of protein immunogenicity. One of the most direct causes of ICIs failure to treat tumors (primary or secondary resistance) is the lack of highly immunogenic tumor-specific antigens, resulting in T cell failure. Theoretically, tumors with high mutational burden have a higher probability of producing more new antigens with sufficient immunogenicity to induce antigen-specific T-cell responses. Studies have shown that the more effective the formed tumor-specific antigen is, the better the efficacy of ICIs will be, and this is related to the progression-free survival of patients. Immune checkpoint-blocking tumor therapy has a higher incidence of drug resistance than molecular targeted drugs. Among many drug resistance mechanisms, there have been many reports on the regulation of TME (tumor microenvironment), intracellular protein mutations, oncogene signal transduction pathways, epigenetic changes, and other related studies. However, in clinical practice, they only partially improve the ICB resistance of tumors, making it difficult to obtain universal biomarkers. At present, it is considered that due to the complexity of drug resistance mechanisms, it is no longer clinically significant to simply identify and regulate drug resistance targets, and drug resistance may even occur again soon. It is speculated that according to the possible tumor characteristics, combined with the three treatment methods, the tumor microenvironment ecology should be changed, and various heterogeneous tumor subsets should be eliminated, so as to reduce tumor drug resistance and improve the long-term clinical efficacy [1].

?2. Antigen presentation dysfunction

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The major histocompatibility complex (MHC), called human leukocyte antigen (HLA) in humans, is a very polymorphic genetic complex that encodes cell surface molecules that specifically present and recognize self-and non-self peptides. MHC-I protein presentation is primarily derived from intracellular peptides. The mutant peptides produced by proteasome-mediated endogenous protein decomposition are transported by antigen processing related transporter (TAP) to endoplasmic reticulum (ER), where they can be loaded onto MHC-I. The MHC-II dimER is assembled and bound to invariant chain (Ii) of the er. The Ii-MHC-II complex may be transported directly from the cell surface or internalized indirectly to the MHC-II compartment (MIIC) where Ii is degraded by a series of endosomal proteases, releasing MHC-II for binding to specific peptides derived from muteins that decompose in the endosomal pathway. These pMHC complexes will be transported to the cell surface, where they will be recognized by T cells [2]. Cancer cells can escape the immune system by down-regulating or losing the expression of protein, an antigen recognized by immune cells. This may be because mutations in cancer cells affect the expression of these protein, or because cancer cells produce an immunosuppressive microenvironment that prevents immune cells from recognizing and attacking cancer cells. Cancer cells can also escape the immune system by changing their ability to process and present antigens, resulting in immune escape?[3].

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3.CD8+T cell depletion

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T-cell failure is considered to be a dysfunction state caused by the immunosuppressed tumor microenvironment and the long-term existence of tumor antigens, and continuous antigen stimulation leads to T cell depletion, while CD8+T cell depletion is considered to be one of the most important causes of tumor immune resistance, with complex mechanism, and new hypotheses are constantly proposed [5].

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4.Tumor microenvironment inhibition

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Tumor cells induce the surrounding environment to inhibit anti-tumor immunity, and immunosuppressed cells, cytokines and tumor metabolites constitute the external factors of tumor drug resistance. Three types of immunosuppressive cells are currently known: (1) Regulatory T cells, the main immunosuppressive subgroup of CD4+T cells, induce high-level PD-1 expression in CD8+T cells and cause the tumor to escape from anti-tumor immunity. (2) Bone marrow-derived suppressor cells are a group of immature myeloid cells that have the inhibitory ability in the tumor microenvironment, inhibiting the effector T cell response and inducing Treg cell expression. (3) Tumor-associated macrophages: they are divided into two phenotypes, i.e., M1 type involved in the promotion of anti-tumor immunity and M2 type with pro-cancer properties. PD-1 can be expressed on TAMs membrane, and is mainly of M1 type. Clinical studies have confirmed the correlation between the increase of TAMs and adverse clinical outcomes, and targeted TAMs is expected to induce tumor regression?[6].

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PART02

Solutions for immunotherapy resistance

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1. Immune combined with anti-angiogenic drugs

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The application of immune drugs combined with anti-angiogenic drugs in solid tumors has been common, especially in liver cancer, kidney cancer, endometrial cancer has been widely approved. One of the differences between neoplastic neovasculature and non-malignant tissues is its abnormally tortuous structure, which leads to perfusion disorders within the tumor, leading to a more hypoxic and acidic TME. Second, it has high vascular permeability. The compression of tumor cells and extracellular matrix on blood vessels, as well as poor lymphatic drainage system, leads to reduced blood flow, impeding the entry of immune cells and drug accumulation. Antiangiogenic drug are thought to "trim" that new tumor blood vessels or prevent their formation. The theory of antiangiogenic drug-induced angiogenesis normalization provides a potential theoretical basis for the addition of antiangiogenic drugs to ICI. According to the unique TME internal characteristics of each tumor type, it may be critical to select the optimal antiangiogenic drug as the joint partner of ICs. The same factors should be considered when choosing ICI as an antiangiogenic partner (e.g., PD-1vsPD-L1)[7].

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2. Immunization combined with chemotherapy drugs

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DNA destroy agents can increase that immunogenicity of canc cells by adding new antibodies and change the cytokine environment in the tumor microenvironment, thereby lead to increased redistribution and expression of PD-L1 on tumor cells. The combination of PD-1 inhibitors with chemotherapy has worked well in the treatment of solid tumors and lymphomas. A clinical result suggests that cetuximab and paclitaxel are effective and safe to control the recurrence or metastasis of head and neck squamous cell carcinoma that progresses after ICIs treatment?[8]. Experiments have shown that cyclophosphamide and vinorelbine can activate dry CD8+T cells and improve the anti-PD-1 efficacy of triple-negative breast cancer.

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3. Double immune combination

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Ibimumab is a monoclonal antibody against the CTLA-4 inhibitor and Nivolumab is a monoclonal antibody against PD-1. Nivolumab+ipimumab has become a first-line option for immunotherapy for colorectal cancer, and this is a successful case of dual immune combination therapy. CTLA-4 and PD-1 have different mechanisms of action and play complementary roles in regulating adaptive immune responses. PD-1 exhausts peripheral T cells, while CTLA-4 mainly inhibits T cell activation in the early stage. Therefore, anti-CTLA-4 antibodies can synergize with anti-PD-1 antibodies in clinical practice. Although many clinical trials have proved that double immune combination therapy has a higher response rate and considerable safety, but its application in immunotherapy after drug resistance treatment of clinical research is just beginning. It is expected that more successful combinations of double-immune combination therapy will appear in the future.

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4. Other possible option

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In addition to the above strategies, the use of immune drugs in combination with radiotherapy and anti-HER2 drugs has also proved to be effective, but attention should be paid to the indications of the approved drugs and the experimental beneficiary populations. In addition, the combination therapy of T-VEC oncolytic virus combined with epimab [9], MDM2 oncogene inhibitor combined with PD-1 inhibitor pabolizumab [10]?also shows certain prospect. This method still needs to be verified by large-scale clinical research.

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Immunotherapy has a complex mechanism. In theory, there are many combination therapies available. However, limited by the cognition of existing research and clinical practice, the currently available combination therapies are mainly combined with anti-vascular inhibitors. This scheme has also become one of the options for patients to go to chemotherapy clinically. At the same time, it has become the first-line treatment option for driving gene negative or driving gene positive resistance in some cancers. With the increasing attention paid to immunotherapy, it is believed that more combination therapies benefiting tumor patients will be approved in the future for the benefit of more people.

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References

[1] Cancer Med. 2020; 9(21):8086-8121

[2] Viral Immunol. 2020; 33(3):160-178.?

[3] J Cancer Res Clin Oncol. 2023; 149(10):8131-8141.?

[4] Signal Transduct Target Ther. 2023; 8(1):9.

[5] Immunity. 2018; 48(3):434-452.?

[6] Front Oncol. 2020; 10:188.

[7] Nat Rev Clin Oncol. 2024; 21(6):468-482.

[8] Medicina (Kaunas). 2021; 57(11):1151.

[9] Sci Transl Med. 2019; 11(515):eaat5025.

[10] Cell Death Discov. 2021; 7(1):90.

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