https://orcid.org/0000-0002-6715-9986
Abstract
Purpose: To assess the impact of neoadjuvant chemotherapy (NACT) on the tumor immune microenvironment (TIME) in gynaecological tumors, with a focus on understanding the potential for enhanced combination therapies.
Methods: We systematically queried the PubMed, Embase, and Cochrane databases, encompassing reviews, clinical trials, and case studies, to undertake a thorough analysis of the impact of NACT on the TIME of gynaecological tumors.
Results: NACT induces diverse immune microenvironment changes in gynaecological tumors. In cervical cancer, NACT boosts immune-promoting cells, enhancing tumor clearance. Ovarian cancer studies yield variable outcomes, influenced by patient-specific factors and treatment regimens. Limited research exists on NACT’s impact on endometrial cancer’s immune microenvironment, warranting further exploration. In summary, NACT-induced immune microenvironment changes display variability. Clinical trials highlight personalized immunotherapy’s positive impact on gynaecological tumor prognosis, suggesting potential avenues for future cancer treatments. However, rigorous investigation is needed to determine the exact efficacy and safety of combining NACT with immunotherapy.
Conclusion: This review provides a solid foundation for the development of late-stage immunotherapy and highlights the importance of therapeutic strategies targeting immune cells in TIME in anti-tumor therapy.
KEY MESSAGES
The abnormal tumour microenvironment in gynaecological tumours can impede the penetration and accumulation of chemotherapeutic drugs, leading to poorer drug therapy efficacy.
Neoadjuvant chemotherapy can improve the surgical resection rate of patients while regulating the ratio of each immune cell subpopulation to achieve the regulation of the tumour microenvironment, thus achieving anti-tumour effects.
Based on the immune variability of patients after neoadjuvant chemotherapy, selecting the most suitable individualized immunotherapy will become a promising new therapy.
Introduction
NACT is an essential component of the comprehensive treatment of advanced malignant tumours. It was first proposed by FREI [Citation1] in 1982 and referred to several courses of systemic chemotherapy treatments prior to radiotherapy or surgery in order to lessen the tumour load in advance to facilitate subsequent surgery, radiotherapy, or other related therapies. Because of its high sensitivity and good curative effect, NACT has been widely used in many tumours, such as lung cancer, breast cancer, head and neck cancer, gastrointestinal cancer, osteosarcoma, and so on. In the field of gynaecological tumours, it has also become an essential part of the comprehensive treatment of cancer patients [Citation2–9].
People have regarded tumours as isolated masses that exist alone in an organ’s specific location until oncologists discovered the tumour microenvironment (TME), which includes immune cells, major signalling molecules, and extracellular matrix [Citation10–12]. Among them, the TIME, which includes innate and adaptive immune cells, extracellular immunological factors, and cell surface molecules, is highly correlated with tumour formation, development, recurrence, and metastasis [Citation13–15].
Chemotherapy is a conventional treatment for most malignant tumours, which effectively inhibits the mitosis and nucleic acid anabolic processes of tumour cells and directly interferes with the deoxyribonucleic acid (DNA) replication of tumour cells [Citation16]. Recently, a growing number of studies have shown that chemotherapy also has immunomodulatory effects, promoting lymphocyte activation and reducing the production of inhibitory immune cells.
Due to the ease of access to paired tumour samples before and after chemotherapy, NACT has become an excellent clinical model for evaluating the impact of chemotherapy on TIME, giving a theoretical foundation for NACT in combination with immunotherapy. By outlining the differences in tumour-infiltrating immune cells before and after NACT treatment, efficacy prediction, and corresponding prognostic value, we highlight the influence of NACT on TIME in gynaecological cancers and its possibility of combination immunotherapy in this paper [Citation17,Citation18].
2. Clinically meaningful TIME composition
Numerous immune cells, including adaptive and innate immune cells, are present in TIME. The former consists of T cells and B cells, whereas the latter is primarily comprised of natural killer cells (NKs), neutrophils, dendritic cells (DCs), macrophages, myeloid-derived suppressor cells (MDSCs), etc. These cells can function as either tumour antagonists or agonists. It is true even though these immune cells often destroy tumour cells at an early stage. Tumour cells can evade immune surveillance by altering the expression of surface antigens, secreting immunosuppressive factors, or influencing the migration of tumour cells. They can even devise ways to impede the function of tumour immune cells, thereby reducing the effectiveness of anti-tumour therapy.
2.1. Adaptive immune cell
T lymphocytes play an essential role in the immune system of cancer patients. CD4+ T lymphocytes produce various cytokines, and CD8+ T lymphocytes can directly kill cells infected by viruses, bacteria, and tumour cells expressing specific antigens. Pfirschke et al. [Citation19] demonstrated that immunogenic chemicals can efficiently stimulate the immune response of the T lymphocytes. Secondly, some scholars have proposed that senescent CD8+ T cells play an important role in anti-tumour immunity [Citation20], due to their crucial role in immunosuppression and tumorigenesis development [Citation21,Citation22]. Recent studies have shown that γδ T cells are a unique type of innate immune T cells that can directly recognize tumour-associated antigens and are not restricted by the major histocompatibility complex (MHC), enabling rapid and direct killing of tumour cells. In addition, it can secrete various cytokines and regulate anti-tumour immune responses through cellular interactions. Therefore, γδ T cells are considered to be one of the best candidates for use in immunotherapy [Citation23]. Although the majority of studies have currently focused on T cells, there is evidence that B cells have an indispensable effect on tumour control [Citation24]. In tumour-related tumour-infiltrating lymphocytes (TILs), both T and B cells can interact and synergistically promote each other. Moreover, it has been postulated that the latter can deliver homologous tumour-derived antigens to the former and that the two cells can work together to promote the development and intensification of immune behaviour [Citation25,Citation26].
2.2. Innate immune cells
Innate immunity can rapidly identify pathogens in the body, with NKs serving as the first line of defence. It can secrete perforin, enzyme granules, and cytokines that can identify or eliminate inflammatory and tumour cells, and it has an anti-tumour immunosurveillance function [Citation27,Citation28]. Neutrophils are the most abundant type of white blood cell in the human circulatory system and are enriched at various tumour lesions [Citation29]. It has been reported [Citation30] that neutrophils play a significant role in chronic inflammatory diseases, including cancer, and possess greater viability and more elaborate functions, especially within the TME [Citation31]. Recent studies have reported that neutrophils exhibit heterogeneity in the expression of transcriptome and surface differentiation antigens in mouse models, the presence of both N1 (tumour suppressor) and N2 (tumour promoter) phenotypes and how to select neutrophils with immune-promoting properties based on different molecular markers will be a new direction to explore [Citation32–34]. The most potent and specialized antigen-presenting cells (APCs) in the immune response are DCs [Citation35,Citation36]. There must be a large number of cytokines in the TME that negatively affect DCs and their normal immune function, according to an increasing number of studies. Macrophages originate from monocytes and are crucial for immune defence, surveillance, and regulation [Citation37,Citation38]. It can exhibit two types: classically activated inflammatory M1 and alternately activated immunosuppressive M2 [Citation39]. Related studies have shown that tumour macrophages can reduce the efficacy of chemotherapy, but the mechanism is still controversial [Citation40,Citation41]. MDSCs are a group of bone marrow-derived immunosuppressive cells [Citation42,Citation43]. Despite the fact that numerous chemotherapies can deplete MDSCs, it has been discovered that chemotherapeutic medications can augment the effects of MDSCs [Citation44,Citation45]. The duality of chemotherapeutic pharmaceuticals requires additional research.
3. Mechanisms of commonly used chemotherapeutic drugs
Surgery, radiotherapy, and chemotherapy have always been necessary for treatment as the three pillars of treating gynaecological malignant tumours. With the in-depth development of clinical pharmacology, immunology, molecular biology, genetic engineering, and oncological clinical research, the continuous emergence of new anti-tumour drugs has made oncological chemotherapy the fastest growing but the most clinically relevant and controversial part of the gynaecological oncological treatment process. In 1996, paclitaxel analogues showed apparent efficacy in advanced ovarian cancer, especially in cisplatin-resistant patients, which aroused attention. Subsequently, due to the obvious drug resistance and toxic side effects of paclitaxel, more new chemotherapeutic drugs have been introduced one after another, so that oncology treatment has developed from the original single drug to a combination of drugs, and at the same time, the efficacy of immunotherapy based on the tumour immune microenvironment has also begun to see the first signs of its effectiveness, and the original standardized drug use has changed into a more emphasis on individualized precision therapy in clinical practice. In the following, the research progress of common chemotherapeutic drug mechanisms in gynaecological tumours is summarized and their applications are prospected.
3.1. Taxoids
On the one hand, orean can play an anti-tumour role by stabilizing tubulin to inhibit cell division; on the other hand, they can act as lipopolysaccharide mimics and switch macrophages from immunosuppressive mode M2 to M1 in a toll-like receptor 4 (TLR4)-dependent manner, enhancing the patient’s ability to kill tumour cells [Citation46]. Similarly, as a potent immune activator, it can enhance the capacity of DCs to present antigens via DC-dependent IL-12 gene expression, thereby enhancing CD8+ T-cell expression. In addition, studies found that it can also inhibit the function of immunosuppressive cells (regulatory T cells), recruit lymphocytes, and stimulate the release of cytokines. The aforementioned mechanisms may increase immunotherapy’s anti-tumour efficacy [Citation47].
Moreover, because conventional paclitaxel preparations have the same concentration distribution in tumour and normal tissues, resulting in many serious adverse effects, nanoparticle albumin-bound paclitaxel (nab-P) both specifically enrich tumour tissue through enhanced permeability and retention (EPR) effects [Citation48] and activates gp-60 receptors on vascular endothelial cells, causing endothelial cells to dimple into nests [Citation49], then transferring nanoparticles into the tumour cell space. Subsequently, intercellular interstitial albumin nanoparticles are mediated by secreted protein acidic and rich in cysteine (SPARC) into the interior of tumour cells, reversing the immunosuppression of TME and exerting anti-tumour effects by enhancing the antigen-presenting ability of APCs, indirectly promoting T-cell activation, and synergizing cytotoxic T lymphocyte killing [Citation50,Citation51], and also allowing macrophages to take up by way of micropinocytosis paclitaxel, which switches macrophages from immunosuppressive M2 cells to immune-activating M1 cells in a TLR4-dependent manner[Citation52], increasing the body’s ability to kill cells and exert anti-tumour effects.
3.2. Platinum
Platinum is the primary drug for the chemotherapy of gynaecological tumours. Carboplatin combined with paclitaxel is the preferred standard chemotherapy for epithelial ovarian cancer (EOC), and cisplatin is the first choice for chemotherapy in endometrial cancer. Platinum drugs have been developed for three generations since the 1960s.
Studies in two multifunctional mouse ovarian cancer models found that the first-generation platinum drug cisplatin can regulate the immune environment through the cGAS/STING pathway and, combined with programmed death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade can increase the survival rate of mice with invasive tumours [Citation53]. Second-generation carboplatin induces DNA damage, activating the typical STING/TBK1/IRF3 pathway and the atypical STING-NF-κB signalling complex. Recently, it has been reported that low-dose carboplatin transforms ‘‘cold’’ tumours into ‘‘hot’’ tumours through the signal-centre STING, enhances innate and adaptive immunity, promotes the maturation and production of immune cells such as CD8+ T cells, DCs, and NKs, and increases PD-L1 expression, thereby triggering practical anti-tumour effects [Citation54,Citation55]. Third-generation oxaliplatin is a novel platinum-based anticancer drug that causes apoptotic cells to leak adenosine triphosphate (ATP) outside the cell. Leaking ATP can attract DCs and macrophages to the tumour site and activate DCs, greatly enhancing their ability to deliver antigens. ATP can not only induce the secretion of IL-1β and promote the activation of CD8+ T lymphocytes but also activate the expression of programmed death-ligand 2 (PD-L2) through the JAK-STAT signalling pathway [Citation56,Citation57].
In addition, to avoid side effects and high drug resistance, platinum is embedded in a specially designed nanoparticle, and it has been discovered that cisplatin nanomedicine can not only induce continuous high expression of major histocompatibility complex-I (MHC-I) and promote the formation of peptide major histocompatibility complex (pMHC) to activate the antigen presentation pathway further, but it can also activate the proliferation and activation of CD8+ T cells in tumours via the T-cell receptor signalling pathway, thereby inducing a more robust anti-tumour immune response [Citation58].
Recently, there has been a new way of programmed cell death – pyroptosis. Researchers have found that as long as a small part of tumour cells pyroptosis, is enough to stimulate the inflammatory response, improve the TIME, and then activate the powerful T-cell anti-tumour immune response. Based on this, Shao’s team believes that the inflammation caused by pyroptosis will trigger a potent anti-tumour immune response and achieve synergistic anti-tumour effects with immune checkpoint inhibitors (ICIs) [Citation59]. Studies have shown that cisplatin, lobaplatin, doxorubicin, and other chemotherapeutic drugs can cause pyroptosis of cervical cancer HeLa cells by activating caspase-3 and cleaving gasdermin E (GSDME), exerting anti-tumour effects [Citation60–62].
3.3. Other chemotherapy drugs
For more than 20 years, the prognosis of patients with gynaecological tumours has been significantly improved with the standardized application of chemotherapy and maintenance therapy based on paclitaxel and carboplatin [Citation63]. Data show that most patients with advanced ovarian cancer will experience recurrent recurrence or disease progression. With the shortening of platinum-free interval (PFI), platinum-resistant recurrence will eventually occur, which is very difficult to treat clinically [Citation64]. Given this, other chemotherapeutic agents targeting platinum resistance and the toxic effects of paclitaxel have been developed.
Gemcitabine is a safe and limited drug for treating recurrent ovarian cancer in platinum-sensitive and resistant patients [Citation65]. It has been found to sensitize tumour cells to ICIs by enhancing the synthesis of antigen-presenting and pro-inflammatory chemokines and increasing the proportion of CD8+ and CD4+ T cells, thereby inducing apoptosis and PD-L1 expression [Citation66,Citation67]. Recent studies have shown that low-dose gemcitabine exclusively inhibits TI-Tregs and prolongs survival in immunoreactive mice, helping to overcome the suppressive effects of treg immune cells in TME [Citation68]. In conclusion, the combination of gemcitabine and immune checkpoint inhibitors has synergistic anti-tumour effects.
Cyclophosphamide not only alters pro- and anti-phagocytic factors in macrophages but also increases the expression of various cytokines (VEGF, IL-16, etc.) in the bone marrow and activates multiple genes, specifically recruiting macrophages and enhancing macrophage phagocytosis [Citation69]. Fluorouracil has been shown to induce immunogenic cell death (ICD) in tumour cells, but in vivo, immunotherapy is not practical due to its drug resistance and low selectivity. It has been found that the metal-fluorouracil network induces iron death, which acts as an immune inducer, maturing immune cells in the spleen and infiltrating CD8+ T cells inside tumours, which has a significant inhibitory effect on the growth of tumours in loaded mice, achieving synergistic immune activation [Citation70]. Given the extensive clinical use of etoposide in oncology and the ability of tumour cells treated with it to induce interferon production by DC-mediated T cells. It can be deduced that intra-tumoural administration of etoposide may enhance DC function in vivo by increasing the immunogenicity of tumour cells, which in turn is expected to induce antigen-specific T-cell expansion in vivo, especially when combined with systemic ICIs [Citation71].
4. Effect of NACT on the immune microenvironment of gynaecological tumours
4.1. Cervical cancer
Paclitaxel plus cisplatin is presently recognized as the most effective NACT chemotherapy regimen for patients with cervical cancer, but its pathologic complete response (pCR) is only 10% to 17%. Therefore, NACT is only used for patients with early cervical cancer in areas where radiotherapy apparatus is unavailable and advanced medical evidence is lacking. Similarly, NACT is reserved for patients with advanced cervical cancer as a tertiary recommendation. Recent studies have demonstrated that NACT based on cisplatin plus paclitaxel has a unique impact on cervical cancer TIME, which may explain why NACT for cervical cancer is ineffective [Citation72,Citation73]. This section summarizes the alterations in the cervical cancer immune microenvironment before and after NACT.
Multiple immune markers were measured before and after platinum-based NACT, and it was determined that CD4, CD8, CD20, and CD56 were significantly elevated in the samples after chemotherapy, indicating that preoperative chemotherapy did transform cervical lesions into sites for anti-tumour immunity [Citation74]. In a separate study, stromal TILs, primarily CD3+ and CD4+ T helper cells, were found in all cases, which significantly increased the immunogenic potential of cervical cancer [Citation75]. In addition, studies have found that a high proportion of intratumoural CD8+ T cells/stromal Foxp3+ T cells is an independent prognostic factor for progression-free survival (PFS) and overall survival (OS). The balance or interaction of CD8+ and Foxp3+ T cells in the TME determines clinical outcomes rather than the absolute number of TILs [Citation76,Citation77].
PD-L1 expression was also increased after chemotherapy in cervical cancer [Citation75,Citation78–80], and was found to be associated with high CD8+ TILs. Additionally, patients with reduced PD-L1 expression had a trend toward longer survival. Increased PD-L1 expression after chemotherapy and a lymphocyte-dominated microenvironment provides a rationale for the combination of anti-PD-1/PD-L1 antibodies in NACT for cervical cancer patients, according to the studies cited above. In contrast, one study found a correlation between low PD-L1 expression and decreased TILs after NACT [Citation81].
In addition to focusing on T cells, some studies have found that chemotherapy increases the number of macrophages and neutrophils [Citation82]. A survey of NACT in 24 patients with advanced cervical cancer found that 13 patients with good clinical responses to treatment had a higher number of NKs before NACT, which could be used as a predictor of NACT efficacy [Citation83]. Another study found that NACT can effectively reduce the neutrophil/lymphocyte ratio (NLR) of IB2-IIB cervical cancer [Citation84].
In conclusion, NACT stimulates the anti-tumour immune response in patients with advanced cervical cancer. Combining it with immunotherapy may become an effective option to break through the bottleneck of NACT treatment for cervical cancer.
4.2. Ovarian cancer
Primary debulking surgery (PDS) combined with postoperative adjuvant chemotherapy remains the standard treatment modality for advanced EOC. In recent years, with increasing research on NACT by domestic and international experts, the role of combining it with interval debulking surgery (IDS) in patients with advanced EOC has received increasing attention. It has been shown that NACT followed by IDS in patients with advanced EOC has comparable survival to PDS. NACT improves survival outcomes, increases the likelihood of achieving adequate tumour cytoreduction, and reduces perioperative complications. National Comprehensive Cancer Network (NCCN) guidelines have recommended NACT as early as 2011. Recent guidelines have again suggested that hyperthermic intraperitoneal chemotherapy (HIPEC) combined with IDS and NACT is a safe option that significantly improves 5-year OS and PFS [Citation85–87].
Lodewijk et al. [Citation88] found that not only functional cells but also exhausted cells increased after NACT, and the increase of the functional immune cell population was significantly more significant than that of the exhausted cell population. Recently, researchers conducted an empirical investigation on 150 ovarian cancer patients. NACT has been shown to substantially increase the infiltration of stromal CD3+ and CD8+ cells, as well as intraepithelial CD8+ and CD68+ cells. Similarly, a high proportion of CD8/Foxp3, CD3/Foxp3, and CD68/CD163 was observed to significantly ameliorate PFS after NACT [Citation89]. Polcher et al. detected intraepithelial TILs in 30 ovarian cancer patients prior to and following NACT treatment. The results demonstrated that CD8+ (2.5 times), CD4+ (2.5 times), and granzyme B+ (2.5 times) cells increased substantially, whereas Foxp3+ cells did not demonstrate a significant trend of quantitative change [Citation90]. In contrast, Suarez Mora’s study revealed that B cell function is upregulated during chemotherapy, the Th2 immune response is activated, and the Th1 immune response is suppressed [Citation91]. In addition, an analysis of 147 patients with high-grade serous ovarian cancer (HGSOC) revealed that after NACT, the degree of immune infiltration in HGSOC increased, resulting in a significant number of CD8+ T cells with immune activity. Nevertheless, increased TILs infiltration did not enhance survival, which may be related to the increased proportion of Foxp3+ Tregs, indicating that changes in TIME during NACT may result in immunosuppression [Citation92]. Moreover, IL2Rahi-CCL22+-Tregs increased in tumours following NACT and could inhibit other CD4 and CD8+ T cells via the CD274-PDCD1 axis, resulting in an immunosuppressive state after NACT [Citation93]. These investigations demonstrate that NACT has both immunostimulatory and immunosuppressive properties in ovarian cancer. In addition, increased CD3+, CD8+, and CD163+ cells were found to be associated with improved PFS and OS [Citation94,Citation95].
Despite the fact that the majority of studies indicate that TILs levels change substantially after NACT [Citation96,Citation97], some experiments have failed to find significant differences. Bohm et al. analysed 54 patients with high-grade serous carcinomas (HGSC) and found no significant difference between CD8, CD4, CD3, and CD45+ 7nk density before and after NACT [Citation98]. Similarly, Brunekreeft et al. observed no change in circulating immune cell levels in blood collected before and after chemotherapy, indicating that the tissue of origin may define the immune environment in patients with ovarian cancer and is unrelated to chemotherapy. While the study by Lo et al. [Citation99] showed that chemotherapy could increase the level of TILs in TILs-positive tumours. TILs-negative tumours are still TILs-negative after NACT, suggesting that preoperative tissue biopsy of TILs helps to identify ‘‘immune inert’’ tumours that are ineffective for immunotherapy.
For PD-1 and PD-L1, Mesnage et al. discovered that PD-L1 expression rose following NACT in ovarian cancer, but that PD-L1 expression did not alter prognosis [Citation100]. Another immunological examination of ovarian cancer patients yielded similar results [Citation101]. There was no significant difference in epithelial PD-1 expression before and after chemotherapy, possibly due to the lack of appropriate antigen recognition by MHC-I. Consequently, a strategy to upregulate MHC-I during or after NACT may improve the outcomes for these patients [Citation102].
In addition to examining the expression of TILs and PD-1/PD-L1, several studies have focused on the alterations of other immune cells. According to studies, NKs infiltration increases after NACT [Citation103], and high-density NKs are associated with better recurrence-free survival (RFS) and OS in recurrent cancer [Citation104]. Although the total number of macrophages is decreased following NACT, the adaptive immune response can be aided by transforming tumour-associated macrophages into an anti-tumour M1 phenotype. C3aR+ CD68+ macrophages after treatment are closely related to PFS [Citation105–107]. In addition, monocytes and cytotoxic T cells significantly increased during NACT, indicating that they can be used as immune environment drivers during chemotherapy [Citation108]. Studies have shown that changes in NLR during treatment can be used as a predictor of NACT response in patients with advanced ovarian cancer [Citation109,Citation110].
Despite some discrepancies between the results of the above studies, it is unavoidable to acknowledge that the aggregation of TILs in ovarian cancer is an essential factor affecting survival. In addition, ovarian cancer exhibits a high degree of heterogeneity in its local immune microenvironment, so tumour lesions within the same patient may present significantly different immune phenotypes, that is, bipolar variability from one extreme of immune activation to the other extreme of complete immune rejection. Further studies in larger populations are still needed to clarify the immune changes that occur in TIME after NACT. In conclusion, when designing a combination therapy regimen, it is not only necessary to select appropriate immunotherapeutic agents according to the immune status of the tumour after NACT but also to carefully choose the type of chemotherapeutic agents to control the toxicity of the combination therapy.
4.3. Endometrial cancer
The use of NACT in intermediate to advanced endometrial cancer has been controversial. RESNIK et al. [Citation111] were the first to report using NACT to treat endometrial tumours, suggesting that this therapy is advantageous for treating advanced uterine papillary plasmacytoma. This was followed by the publication of three case reports detailing the tumour’s initial response to NACT, the viability of maximal resection, and its relatively extended survival [Citation112–114].
Following this, the majority of studies on NACT for endometrial cancer have focused on median OS, PFS, and postoperative complications, while fewer studies examine alterations in the immune microenvironment following NACT treatment. Thus, works concentrated on the alterations in the immune microenvironment are urgently needed concentrate on the modifications in the immune microenvironment to develop more effective clinical programs for endometrial cancer patients.
5. Combination of NACT and immunotherapy
NACT can regulate the TME by adjusting the proportion of each immune cell subset to accomplish the goal of tumour immunotherapy. Choosing the most appropriate individualized immunotherapy for patients based on the immune disparities between patients after NACT will become a promising new therapy. Currently, there are three main categories of tumour immunotherapy: ICIs, chimeric antigen receptor T-cell (CAR-T) treatment, and tumour vaccines.
5.1. ICIs
Immune checkpoint inhibitors, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), PD-1, and its ligand (PD-L1) inhibitors, are today’s most prevalent clinical applications. ICIs inhibit and block the binding of heterogeneous checkpoints to their complexes, stimulating the activity of immune cells and achieving the anti-tumour effect. By enhancing tumour antigen release and normalizing vascular function, NACT can increase T-cell infiltration of the TME, thereby providing a target for ICIs.
In cervical cancer, it has been demonstrated that the addition of sintilimab to NACT regimens resulted in markedly higher pCR and overall response rate (ORR) with tolerable adverse effects [Citation115]. At the 2022 European Society for Medical Oncology (ESMO) Congress, Martin’s academician team explored the efficacy and safety of NACT combined with camrelizumab in patients with locally advanced cervical cancer, and the results showed that this neoadjuvant chemotherapy-immunotherapy significantly increased ORR and pCR, with substantially better efficacy and manageable toxicity than conventional regimens [Citation116]. On June 29, 2022, cadonilimab was officially approved as an emerging dual antibody for patients with recurrent or metastatic cervical cancer who have failed previous platinum-containing chemotherapy. Not only can it bind to PD-1 and inhibit the immunosuppressive signalling pathway of PD-1/PD-L1, but it can also efficiently restore the tumour-killing function of T cells. It can also simultaneously or singly bind to CTLA-4, block the inhibitory signalling pathway between CTLA-4 and B7, and effectively promote the activation of T cells. The phase-III clinical study of NACT is ongoing [Citation117]. At this point, cervical cancer has wholly entered the era of immunotherapy.
For ovarian cancer, studies have found that NACT can increase the levels of immune checkpoint molecules PD-1 and CTLA-4 on CD4+ and CD8+ T cells as well as PD-L1 ligand levels on tumour-infiltrating immune cells. And it was discovered that blocking the PD-1/PD-L1 axis would suppress regulatory T cell function and increase the anti-tumour effects of CD4+CD25+ T cells [Citation98]. In a trial(chemotherapy plus durvalumab and tremelimumab), an ORR of 95.6% was observed, and no significant adverse effects were shown [Citation118]. Thus, ICIs, in combination with chemotherapy, will offer new hope for patients with EOC receiving neoadjuvant therapy [Citation88].
The TOPIC study, a phase III clinical study of pembrolizumab in combination with doxorubicin in advanced endometrial cancer, showed promising anti-tumour activity and a manageable safety profile in patients with endometrial cancer who failed platinum-based chemotherapy [Citation119]. Similarly, in the NRG-GY018 study, neoadjuvant therapy (chemotherapy plus pembrolizumab) showed statistically and clinically meaningful improvement in PFS compared to chemotherapy alone [Citation120,Citation121]. The RUBY trial, published simultaneously, demonstrated that dostarlimab, in combination with chemotherapy, significantly improved PFS in patients with primary advanced or recurrent endometrial cancer and included women with sarcomas with a more extended follow-up period [Citation122]. In summary, immunotherapy combined with chemotherapy has also shown great potential in the first-line treatment of stage III-IV or recurrent endometrial cancer, which is worthy of most patients’ expectations.
In conclusion, selecting appropriate ICIs for different targets can significantly improve the immune effect. The combination of chemotherapy and immunotherapy is expected to enhance and synergistically increase the anti-tumour effect of any single therapy [Citation123,Citation124]. At present, clinical trials of chemotherapy combined with immunotherapy have been carried out in a variety of gynaecological tumours, summarized in .
Table 1. Completed clinical trials of chemotherapy combined with immune checkpoint inhibitor therapy.
5.2. CAR-T therapy
CAR-T therapy is a novel immunotherapy capable of precisely targeting tumours, which can directly recognize and bind tumour-associated antigens without relying on MHC molecules and specifically activate T cells to exert anti-tumour effects. It is currently one of the more promising strategies in tumour immunotherapy [Citation125]. Chemotherapeutic drugs such as fludarabine and cyclophosphamide can remove common lymphocyte populations in the body, provide space for CAR-T cells to expand, and eliminate immunosuppressive cells such as Tregs [Citation126]. Preclinical studies have shown that low-dose carboplatin chemotherapy can enhance the killing effect of tumour cells on ErbB-CAR-T cells and improve their outcome [Citation127,Citation128]. Therefore, CAR-T combined with chemotherapy is safer and more effective than CAR-T therapy alone.
A recent study showed that T cells in CAR-T cell therapy could be programmed as tumour-attacking cells, proving effective in ovarian cancer mice. Mesothelin (MSLN) glycoprotein is overexpressed in many solid tumours and is a target for antigen-specific therapy. Many ovarian tumours contain MSLN, and experimental researchers have found that three CAR-T cells (M1xx CAR-T cells, M28z CAR-T cells, and MBBz CAR-T cells) significantly prolong the survival of mice with cancer, among which M1xx CAR-T cells are the most effective. The above studies have shown that immunotherapy involving CAR-T cells attacking mesothelin is a promising treatment for ovarian cancer, and calibration of CAR-T cell activation is also a promising strategy to enhance the anti-tumour function of CAR-T cells [Citation129].
5.3. Tumour vaccines
Studies have shown that almost all tumour patients secrete tumour-specific and individually variable tumour neoantigens, offering new possibilities for precise tumour treatment [Citation130]. A novel cancer vaccine, PDS0101, was recently reported in Cancer Immunology 2022. It was combined with radiotherapy and chemotherapy in 9 high-risk locally advanced cervical cancer patients. The patient achieved a total remission rate of 100% and a tumour volume reduction of more than 60% [Citation131]. Suggesting that combining appropriate vaccines with conventional treatments can eradicate minor lesions, delay recurrence, and restore the vitality of patients with advanced cancer.
6. Conclusion and outlook
The TIME is crucial to the patient’s survival and prognosis. Based on the above studies, NACT affects TIME by controlling the quantity and activity of specific immune cells. In this paper, we highlight the tremendous potential of immunotherapy, the remodelling effect of NACT on TIME, the predictive efficacy of infiltrating immune cells, and their related prognostic significance in gynaecological malignancies (.). By altering the number and function of immune infiltrating cells, NACT is able to influence TIME and boost anti-tumour immunity. On the basis of this, a scientific and judicious selection of individual immunotherapy drugs has been implemented, making it possible to eradicate small lesions to the greatest extent, thereby improving the prognosis of patients with advanced disease, which will become a new treatment method in gynaecological tumours.
Table 2. The changes and prognostic significance of NACT on the immune microenvironment of common gynaecological tumours.
Author contributions
Jing Xue: collection of literature and drafting the paper. Xia Yan: conception and design, revising the paper, final approval of the version to be published. Nan li: revising the paper critically for intellectual content. Menghan Wu: revising the paper critically for intellectual content. Qin Ding: revising the paper critically for intellectual content and the final approval of the version to be published. Jianbo Song: conception and design, revising the paper critically for intellectual content and the final approval of the version to be published. All authors agree to be accountable for all aspects of the paper.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
Data sharing is not applicable to this article as no new data were created or analysed in this study.
Additional information
Funding
References
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