October 20, 2021

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Tumor microenvironment and drug resistance in immunotherapy

Tumor microenvironment and drug resistance in immunotherapy.

The relationship between tumor microenvironment and drug resistance in immunotherapy and its countermeasures



Tumor microenvironment and drug resistance in immunotherapy.

The relationship between tumor microenvironment and drug resistance in immunotherapy and its countermeasures. 

Malignant tumors are one of the main problems that threaten human life and health. In the past, most of the treatments for tumors focused on the tumor cells themselves. In recent years, immunotherapy has mainly achieved anti-tumor effects by regulating the body’s own immune system, which has brought revolutionary progress in the treatment of malignant tumors.

According to different mechanisms of action, tumor immunotherapy is divided into six categories, including: 

  • cytotoxic T lymphocyte-associated antigen 4 (CTLA-4),
  • programmed cell death protein-1 (PD-1) and its ligand (PD-L1) ) 
  • other immune checkpoint inhibitor therapy;
  • chimeric antigen receptor T cell immunotherapy; tumor vaccine;
  • oncolytic virus; bispecific antibody blinatummoab targeting CD3;
  • immune agonist, etc.

However, in current clinical practice, immunotherapy can only bring long-lasting survival benefits to 20%-30% of patients, and most patients will face the problem of immunotherapy resistance.

Therefore, the biggest bottleneck facing immunotherapy is the lack of accurate prediction of dominant populations and the systematic research and response of primary and secondary drug resistance mechanisms, resulting in excessive or insufficient immunotherapy.

The recent in-depth understanding of the interaction between tumor and tumor microenvironment (TME) has given new opportunities for immunotherapy.

Studies believe that the positive response of immunotherapy usually depends on the dynamic interaction between tumor cells and immunomodulators in TME.

More and more studies have shown that the inhibitory changes and heterogeneous characteristics of TME have a huge impact on the occurrence and development of tumors, the difference in efficacy and drug resistance.

TME is a complex ecosystem, composed of various types of cells and their secreted products (such as cytokines, chemokines) and other non-cellular components of the extracellular matrix, with obvious heterogeneity, dynamics and complexity Of cell-to-cell associations.

Effector immune cells, inhibitory immune cells, interstitial components, etc. are all related to the increase in tumor cell proliferation and invasion, increase in drug resistance and decrease in anti-tumor immunity in different links, so it is clarified that all aspects of the TME network coordinate or suppress immune response The mechanism is very important for reversing immune resistance.

This article summarizes the origin, dynamic inhibitory changes, heterogeneity characteristics of TME and its impact on the immune response, and seeks coping strategies to optimize the efficacy of immunotherapy from the perspective of TME.

Tumor microenvironment and drug resistance in immunotherapy.

Tumor microenvironment and drug resistance in immunotherapy


01  The formation and development of tumor microenvironment

The microenvironment surrounding normal human tissues is an important barrier for the body to defend against tumors and can effectively inhibit tumor growth. Tumor cells colonized in normal tissues can change the microenvironment around tumor cells to form TME by recruiting tumor-associated fibroblasts (CAF), regulating immune cells and their secreting factors, and vascular endothelial cells forming new blood vessels.

TME is generally composed of three parts: matrix components, cell components and soluble factors. In the early stage of tumor growth, immune cells and related matrix components recruited and activated by tumor cells can form a tumor-inhibiting inflammatory microenvironment and hinder the development of tumors.

However, with the continuous proliferation of tumor cells and the continuous immune activation response, TME undergoes dynamic changes: immune effector cells are exhausted or remodeled and cannot perform normal functions; tumor cells use the negative regulation mechanism of the immune system to form an immunosuppressive state; plus The activation of tumor-associated fibroblasts, immune cell migration, inhibitory cytokine release, tumor vascularization and other factors form a full range of immunosuppressive TMEs, which can play a role in tumor development and drug resistance.

Promote tumor immune escape, deterioration, increase invasiveness, antagonistic treatment and other effects.


02.  Dynamic changes of tumor microenvironment and formation of inhibitory TME

2.1 The role of matrix components in the changes of tumor microenvironment

Fibroblasts in normal tissues play an important role in maintaining the stability of the tissue structure framework, repairing tissue damage, and inhibiting tumor formation. During the formation and change of TME, normal fibroblasts are transformed into CAF, an important component of matrix components, under the stimulation of many chemokines. Olumi et al. have shown that CAF can directly promote tumor development through in vivo experiments.

In addition, the surface-specific fibroblast activating protein α (FAPα) of CAF can enhance the ability of tumor cells to invade along the fiber and participate in the formation of tumor blood vessels by promoting matrix remodeling, participating in signal transduction such as vascular endothelial growth factor (VEGF), etc. Etc. to form a tumor biological barrier and inhibit the function of effector T cells, thereby promoting tumor progression.

2.2 The role of cellular components in changes in the tumor microenvironment

Tumor cells can inhibit the PD-1/PD-L1 and other signal pathways, secrete interleukin 2 (IL-2), IL-10 and other inhibitory factors through a variety of ways to inhibit the response and function of infiltrating immune cells, and induce immune escape .

In addition, the metabolic remodeling of tumor cells consumes excessive sugar and amino acids, competitively deprives T cells of the nutrients needed, and also promotes the disability and immune suppression of T cells.

On the other hand, the recruitment and expansion of immunosuppressive cells such as regulatory T cells (Tregs), tumor-associated macrophages (TAMs) and bone marrow-derived suppressor cells (MDSCs) in TME is also one of the main mechanisms for inducing immunosuppressive TME. one.

The infiltration of Tregs in tumor tissues can directly inhibit the proliferation of effector T cells and produce inhibitory cytokines such as IL-10 and transforming growth factor β (TGF-β), thereby limiting the anti-tumor immune response and supporting immune escape to promote Tumor progression.

TAMs can induce and maintain the immunosuppressive state of TME by expressing immune checkpoint molecules such as PD-L1, producing immunosuppressive factors such as TGF-β and IL-10, secreting chemokines such as CCL17 and CCL22, and abnormal amino acid metabolism, etc. .

In addition, TAMs can also compete with anti-PD-1 antibodies by recruiting Fc receptors on their surface, leading to immune resistance.

MDSCs strongly inhibit effector T cells by restricting cysteine ​​necessary in the process of T cell activation, breaking down arginine necessary for T cell protein synthesis, secreting immunosuppressive factor TGF-β, and expressing VEGF to promote angiogenesis, etc., to strongly inhibit effector T cells , Natural killer cells and other activities, and stimulate Tregs, thereby mediating immune escape, leading to tumor progression.

2.3 The role of soluble factors in changes in the tumor microenvironment

A large number of soluble immunosuppressive factors in TME is also one of the important mechanisms for tumors to evade immune surveillance.

Soluble factors such as TGF-β, VEGF, chemokines and inflammatory cytokines continue to dynamically change and interact to form a complex network of changes, which together induce functional changes in immune cells and tumor cells, and participate in the induction of angiogenesis in TME.

Interstitial fibrosis, etc., promote immunosuppressive TME, leading to biological behaviors such as tumor proliferation, invasion and metastasis.


03.  Heterogeneity of tumor microenvironment

The development, pathological stages, and treatment stages of different tumors can lead to significant heterogeneity among tumor cells. At the same time, the heterogeneity of matrix components and cell components will further increase the complexity of TME.

3.1 The heterogeneity of matrix components in the tumor microenvironment

The heterogeneity of CAF in tumor stroma components is very common. In solid tumor stroma such as pancreatic cancer and esophageal cancer, the content of CAF is relatively high, forming a high-density extracellular matrix, which increases the fluid pressure between tumor tissues, hinders the absorption of drugs and the intratumoral infiltration of immune cells, leading to different immune responses. In addition, the formation of new blood vessels in the stroma also highlights differences in different tumors and even different stages of the same tumor.

The vascular system in the TME matrix components of liver cancer is relatively abundant, while the neovascular system of pancreatic cancer is relatively lacking; patients with early and advanced renal cancer also have heterogeneity in the density of new blood vessels, the size of vascular endothelial cells and their proliferation ability.

Therefore, it is very important to choose an appropriate treatment strategy according to the characteristics of the stromal components of different tumors.

3.2 The heterogeneity of cellular components in the tumor microenvironment

There is heterogeneity between the cell components of different tumor types and different patients of the same type of tumor, and these differences are affected by many factors.

In terms of phenotype, a study based on the infiltration of immune cells around tumors divided the infiltration of immune cells in TME into immunoinflammatory phenotype, exclusion phenotype and desert phenotype, and proposed that the effect of immune cell phenotype should be used in the treatment process.

The importance of choosing an appropriate treatment strategy. The types of immune cell infiltration of different tumors are also different. Although most tumors are mainly tumor-infiltrating lymphocytes, macrophages infiltrate significantly in patients with pancreatic cancer.

In addition, the infiltration and role of suppressive immune cells are also different in different tumors. Studies in gastric cancer, breast cancer and ovarian cancer believe that the accumulation of Tregs in TME is one of the mechanisms of tumor immune escape. However, the role of Tregs in colorectal cancer is still controversial.

Some studies believe that Tregs infiltration is associated with a good prognosis of colorectal cancer, while other studies are the opposite. Finally, the infiltration of immune cells in tumor TME also presents spatial and temporal heterogeneity, which requires comprehensive analysis during the treatment process.


04.  Response to drug resistance of tumor microenvironment-related immunotherapy

The complex dynamic inhibitory changes and heterogeneous characteristics of TME are an important reason for the uneven level of tumor immunity. In order to solve this problem, the next breakthrough point of immunotherapy is to target the target of immune escape, combining and matching different treatment modes to prepare a “cocktail” therapy of tumor immunity.

4.1 Adjust the matrix components in TME to optimize immunotherapy strategies

CAF-based stromal cells and neovascular system promote tumor progression and drug resistance. Therefore, how to weaken the effect of CAF and reverse the distorted neovascular network is very important to overcome the immune resistance caused by matrix components.

The sibrotuzumab, which targets the FAPA-specific antigen on the CAF surface, has been shown in phase I-II clinical studies to maintain stable disease in patients with advanced FAPA-positive tumors, but the single-agent efficiency remains to be investigated.

In addition, targeted inhibition of protein tyrosine kinase 2 involved in the formation of stromal fibers in mice can increase the infiltration of effector T cells and the arrival of drugs, thereby enhancing immune efficacy and prolonging the survival time of mice. IL-15 activated natural killer cells or CD40 specific antibodies can degrade fibrin and promote immune cell infiltration, thereby enhancing immune efficacy.

From the perspective of abnormal blood supply, hypoxia and low pH, and other TME inhibition states caused by the redundancy of tumor neovascular network in the stroma, the combined application of anti-angiogenic drugs and immunotherapy has also achieved remarkable results.

4.2 Targeting cellular components in TME to optimize immunotherapy strategies

Tregs are important immunosuppressive cells. Targeting depletion of Tregs, inhibiting the function of Tregs, or interfering with the recruitment of Tregs in TME is an effective way to improve the efficacy of tumor immunity. TAMs also show large heterogeneity and multiple inhibitory functions in TME, so blocking their inhibitory effects based on the characteristics of TAMs is also a strategy to enhance immune efficacy.

In mouse models, inhibiting CCR2 by gene knockout or small molecule inhibitor PF-04136309 can inactivate the CCL2-CCR2 signaling pathway and reduce the transport of TAMs to the tumor site, which can reduce tumor growth and metastasis and enhance the efficacy.

In addition, RG7155, which inhibits the CSF-1 receptor, can also reduce the aggregation of TAMs and increase the infiltration of effector T lymphocytes in TME. However, the communication between TAMs and tumor cells involves multiple signaling pathways, so the study of one pathway alone cannot achieve long-term benefits.

It is still necessary to further determine the subgroups of TAMs in the tissue types at different stages of tumor development in order to improve Strategies for targeting TAMs. In addition, indoleamine 2,3-dioxygenase 1 (IDO1), secreted by suppressive immune cells such as MDSCs, is a key target of abnormal L-tryptophan metabolism in TME that affects the therapeutic effect.

IDO1 inhibitor D-1-methyltryptophan (D-1MT) combined with PD-1, CTLA-4 and other immunotherapy has shown a good tumor control rate in mouse brain tumors. At the same time, the combined use of IDO1 inhibitor epacadostat and immunotherapy has shown good efficacy and safety in clinical trials. Targeted formulations of other metabolic enzymes are also worthy of further exploration.

4.3 Targeting soluble factors to optimize immunotherapy strategies

The combined application of immunotherapy for tumor patients with other radiotherapy, chemotherapy, etc. has gradually achieved clinical results.

Doxorubicin and other chemotherapeutic drugs can kill tumor cells through immunogenic cell death pathways, thereby activating anti-tumor immune responses, and can be used in combination with immune agents to achieve synergy; gemcitabine, paclitaxel, etc. can directly act on immune effector cell activation Immune response; 5-fluorouracil can interfere with the function of immunosuppressive cells to reduce immune escape and so on. Intermittent chemotherapy in medium doses may be the preferred combination method, which is worthy of further clinical exploration.

In addition, a study of paclitaxel conjugated to D-1MT showed that conjugated two drugs can significantly improve TME and enhance immune efficacy. In addition, the combination of radiotherapy and immunotherapy can stimulate a systemic immune response to overcome immune resistance.

Early studies have shown that the combination of radiation and ipilimumab can achieve good results, and the mechanism has revealed biological evidence that radiotherapy can activate immunity. There are also case reports showing that ipilimumab combined with radiotherapy can benefit NSCLC patients who have previously failed to receive CTLA-4 alone.

The PACIFIC study also showed that patients who had received thoracic radiotherapy and chemotherapy had a significant progression-free survival benefit compared with the control group when they received the PD-L1 inhibitor durvalumab (HR0.52; 95%CI: 0.42~0.65, P<0.001) ; Especially in patients who received durvalumab within 14 days after radiotherapy, the benefit of immunotherapy was more obvious. Mechanism studies suggest that radiotherapy mainly activates the body’s anti-tumor immune response by promoting the increase in the expression of tumor antigens in situ and the production of new antigens, enhancing the T cell immune response and producing a remote effect.

In addition, the combined application of bevacizumab and other anti-angiogenic drugs has gradually been paid attention to.

A study of the combination of bevacizumab and atezolizumab, paclitaxel and carboplatin in the treatment of NSCLC has achieved good efficacy and safety.

The combination of targeted therapy and immunotherapy has also been explored. A study summarized 13 349 genome maps containing mutations targeted by existing drugs, showing that 8.9% can benefit from combination therapy, but it should be noted that combination therapy Adverse reactions.

In general, the purpose of combination therapy is to reduce the tumor burden while increasing the antigen exposure in TME and the distribution of immune effector cells, transforming the immunosuppressive microenvironment characterization to enhance the immune response, thereby improving the immune efficacy.


Summary and outlook

The inhibitory changes and heterogeneity of TME are important factors that promote tumor progression and affect immune efficacy.

At present, interventions for different components in TME have begun to transform the inhibitory tumor-promoting TME into the tumor-suppressing TME, thereby optimizing the immune efficacy.

However, the tumor immunosuppressive microenvironment is a complex network that is regulated by a variety of immunosuppressive signals and constantly changes dynamically, so simply targeting a certain immunosuppressive signal cannot achieve long-term curative effects.

Screening sensitive markers for different immunotherapy, designing multiple combined targeted immunotherapy strategies, and exploring new immunotherapy targets are bound to be the direction to be explored in the future.

Therefore, continuing to explore the mechanism network of TME on the immune response and exploring new strategies for combination therapy are of great significance for optimizing the efficacy of immunotherapy.

Tumor microenvironment and drug resistance in immunotherapy

(source:internet, reference only)


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