Authors: Changtai Zhao, Rongxin Xiao, Hongming Jin, Xiao Li
Categories: Review, B cell, T cell, ground‐glass nodules, lung adenocarcinoma, tumor immune microenvironment
Source: Thoracic Cancer
Early‐stage lung cancer is now more commonly identified in the form of ground‐glass nodules (GGNs). Presently, the treatment of lung cancer with GGNs mainly depends on surgery; however, issues still exist such as overtreatment and delayed treatment due to the nonuniform standard of follow‐up. Therefore, the discovery of a noninvasive treatment could expand the treatment repertoire of ground‐glass nodular lung cancer and benefit the prognosis of patients. Immunotherapy has recently emerged as a new promising approach in the field of lung cancer treatment. Thus, this study presents a comprehensive review of the immune microenvironment of lung cancer with GGNs and describes the functions and characteristics of various immune cells involved, aiming to provide guidance for the clinical identification of novel immunotherapeutic targets.
Keywords: B cell, ground‐glass nodules, T cell, tumor immune microenvironment, lung adenocarcinoma
A lung ground‐glass opacity (GGO) refers to an increase in turbidity in a specific area of the lung on low‐dose computed tomography (LDCT). ^1^ It can be a pure ground‐glass nodule (pGGN) in the lung, or a part solid nodule (PSN), both of which are collectively referred to as subsolid nodules (SSNs) or ground‐glass nodules (GGNs). The incidence of GGN‐type lung adenocarcinoma (ADC) is increasing due to the gradual popularization of LDCT as a lung cancer screening method. ^2^ , ^3^ Compared to solid nodules (SN), GGNs have different clinical and pathological characteristics. Clinically, GGNs are found to progress more slowly, with Lee et al. detecting 208 GGNs in 160 patients, and 13% of GGNs having growth after 136 months of LDCT follow‐up. ^4^ Another prospective study of the natural course of SSNs showed much less progression of pGGNs, with only 6.6% of 1026 pGGNs developing solid changes after a median follow‐up time of 4.6 years. ^5^ Pathologically, GGN pathologic subtypes are related to their diameter and the percentage of solid component (CTR). Xi et al. found that GGNs with a diameter <20 mm or CTR <50% were characterized by adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA), while adenocarcinomas accounted for more than half of GGNs with a diameter of ≥20 mm or a CTR ≥50%. ^6^ However, it has also been shown that the CT findings of GGNs are not completely consistent with the pathologic findings. ^7^ In general, GGN lung adenocarcinomas (GGN‐ADCs) are slower to progress, less aggressive and relatively inert compared with solid adenocarcinoma (SADC) of the lung.
LDCT can determine the diameter and proportion of the solid component of the GGN, and only persistent or progressive GGNs need to be resected. ^8^ Detterbeck, for example, argues that clinical intervention should be required for GGN diameters greater than 3 cm, or solid components greater than 2 mm or increasing by more than 25% per year. ^9^ However, overtreatment or untimely treatment still exists due to economic cost differences between countries. ^10^ Therefore, the ability to influence GGN progression through noninvasive means could be a revolution in the field of GGN treatment.
With the growing understanding of the tumor immune microenvironment (TIME), immunotherapy has emerged as a significant approach in the treatment of lung cancer. Indeed, the components within TIME collaborate with each other to jointly achieve a balance between antitumor immunity and tumor immune escape. ^11^ Consequently, targeting immune cells in the TIME to enhance the cytotoxic effect of the body's immune system on tumor cells or to inhibit tumor immune tolerance has proven to be an effective means of treating advanced lung cancer. In addition, vaccine formulations composed of immune cells are being developed. Lee et al. showed good application value by transfecting stage III/IV non‐small cell lung cancer (NSCLC) patients' own dendritic cells (DC) with adenoviruses expressing CCL21, and found an increased degree of CD8+ T cell infiltration and high expression of PD‐L1 in tumor cells in the patients after inoculation of the adenoviruses into the tumors. ^12^ However, immunotherapy has not been sufficiently emphasized in GGN lung cancer, an early‐stage lung cancer, and relevant studies are extremely limited. Wu et al. treated 18 patients with advanced lung adenocarcinoma combined with GGNs (N = 37) using anti‐PD‐1/PD‐L1, and after a median treatment time of 7 months, only three patients with GGNs responded to anti‐PD‐1/PD‐L1 treatment, 25 patients with GGNs were unresponsive, and even nine GGN patients demonstrated an increase in diameter or solid component. ^13^ This suggests that PD‐1/PD‐L1 inhibitor therapies may not be applicable to GGN lung cancer, and TIME in GGNs has not been fully explored and summarized. In this review, we summarize the immune microenvironment characteristics of GGNs including T cell, B cell, natural killer (NK) cell and macrophage, DC and granulocyte, aiming to find a new direction for the immunotherapy of GGNs.
T cells are considered the mainstay of tumor immunity, and their different subtypes play different roles in lung cancer. CD8+ cytotoxic T lymphocytes (CTL) recognize tumor antigenic peptide–MHC complexes processed by antigen‐presenting cells (APCs) and destroy tumor cells via the perforin/granzyme pathway or Fas/Fas‐L pathway, which is the core of antitumor immunity. However, in advanced lung cancer, prolonged tumor antigen stimulation and decreased immunocompetence of the body lead to CTL hypofunction and overexpression of inhibitory receptors, ^14^ , ^15^ which in turn leads to tumor immune escapes. CD8+ T cells in GGNs showed a somewhat different tumor‐killing effect than in SN lung cancer. Lu et al. performed single‐cell sequencing (scRNA‐seq) on 12 samples from five patients with GGN‐ADC and five patients with SADC, and less infiltration of CD8+ T cells was observed in GGNs compared with that in SNs, but the expression of CD48, GZMK, LY6E, and IGLC2 were upregulated, suggesting greater activation and expression of higher levels of immune checkpoint molecules in GGNs. ^16^ In another study, the solid, GGO and normal lung tissue component of 12 PSN lung cancer patients were sampled separately, and it was found that there was no difference in the proportions of CD8+ naïve T cells, memory T cells, effector T cells, and exhausted T cells among the three components, but the comparison of cytotoxicity scores similarly illustrated that the cytotoxicity function of CTLs in the GGNs was stronger than that of the SNs and weaker than that of the normal lung (nLung). ^17^ It has also been shown that the percentage of CTLs is higher in GGNs compared to migratory lung adenocarcinoma, although the percentage of total T cells is lower. ^18^ All these studies suggest that CD8+ T cells in GGN‐ADC exert a stronger toxic effect than their role in SADC. More relevant studies are shown in Table 1.
CD4+ helper T cells (Th) play an important paracrine role in activating the differentiation of initial CD8+ T cells into CTLs, while themselves producing cytokines to activate the reactive oxygen species/superoxide pathway in macrophages to mediate antitumor immunity. ^19^ The most common of these subtypes are Th1 and Th2, with the former primarily assisting cellular immunity and providing antitumor immunity, while the latter serves humoral immunity and promotes tumor immune escape. ^20^ One study found that Th1/Th2 skews toward Th2 in NSCLC. ^21^ There is also a type of Th cell that can secrete interleukin 17 (IL‐17) known as Th17. Chang et al. determined that IL‐17 induces inflammation and promotes tumorigenesis in epithelial cells and favors tumor cell proliferation and angiogenesis. ^22^ Compared with SNs, the number of CD4+ T cells was lower in GGNs, and the differentiation of all three subtypes, Th1, Th2, and Th17, was inhibited. ^16^ In addition, Chen et al. performed scRNA‐seq on 101 patients with suspected lung cancer (31 of whom presented with GGNs) and found that the expression of the two Th1‐associated cytokines, interferon‐γ (IFN‐γ) and tumor necrosis factor‐α (TNF‐α), was downregulated in GGNs, suggesting that the Th1/Th2 balance is skewed toward Th2 and promoting cancer immune tolerance in GGNs. ^23^ Overall, the antitumor immune function of CD4+ cells in GGNs was weaker than their role in SNs.
Treg cells can be categorized into two natural Treg (nTreg) and induced Treg (iTreg), both of which can express CD4+ or CD8+, and the Treg in cancer usually referred to CD4+CD25+Foxp+T cells. It can directly suppress immune cells through surface molecules such as CTLA‐4, PD1/PD‐L1, and LAG3. In NSCLC, Treg levels in peripheral blood and local lymph nodes are higher than those in healthy individuals and negatively correlate with prognosis, suggesting an important role of Treg in inducing local immune tolerance, tumor progression, and metastasis in NSCLC. ^24^ Some studies have shown that the proportion of Treg is higher in GGNs than in nLung and lower in GGNs compared to SNs. ^17^ , ^23^ However, several studies found that CD103+CD8+T cells (also known as tissue‐resident memory T cells) and CTLs were proportional to the infiltration of Treg cells in GGNs, and this antitumor immune‐tumor immune escape balance may be responsible for the favorable prognosis of GGN‐ADC. ^25^ , ^26^
In addition, some other subtypes of T cells, such as γδT and NKT cells, also play a role in NSCLC. Both recognize antigens without the restriction of MHC. γδT cells recognize bisphosphonates with their own unique T cell receptor (TCR), ^27^ whereas NKT cells recognize α‐galactosylceramides that have been CD1d‐presented, ^28^ and both show cytotoxic effects on tumor cells. The analysis by Kim et al. of single‐cell RNA sequencing of the GGN component and the nLung component of patients with GGNs showed that both of the above T cells are expressed at a lower level in GGNs than than in nLung, ^29^ and likewise contribute to the generation of an immunosuppressive microenvironment in GGNs, but the relevant studies are insufficiently well characterized and their therapeutic value is not clear.
B cells fulfill different functions at different stages of cancer development. In K14‐HPV16 transgenic mice with genetic defects in T and B cells, de Visser et al. observed a deficiency in innate immune cell infiltration, whereas supplementation of B cells or plasma from normal HPV16 mice restored chronic inflammation, vasculogenesis, and hyperproliferation of epithelial cells in the genetically defective mice, promoting precancerous lesions. ^30^ In a mouse model of metastatic lung cancer, B cell depletion promoted tumor progression, whereas CpG‐induced activation of B cells reduced infiltration of Treg, IL‐10, TGF‐β, and so on, and improved the suppressive immune microenvironment, ^31^ thereby inhibiting tumor progression. Various subtypes of B cells have been observed in the local immune microenvironment of NSCLC, ^32^ with follicular B cell and plasma cell abundance positively correlating with a favorable prognosis. Humoral immunity remains a major function of B cells, with tumor‐associated B cells recognizing tumor‐associated antigens (TAG) and differentiating into plasma cells to secrete antibodies that mediate tumor cell death via antibody‐dependent cell mediated cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC). Meanwhile, cells that play a facilitating role in tumor immune evasion are defined as Breg cells, among which IL10+ Breg exhibit different immune functions in animal models and in humans, respectively, ^33^ and it remains unknown what role Breg actually play in antitumor immunity in lung cancer. It follows that the role of B cells in GGNs is also necessarily bidirectional, and which one dominates is something that needs to be explored. Lu et al. performed gene set variation analysis (GSVA) on the immune function of B cells in GGN‐ADC and SADC, and the results showed that antigen processing and presentation function, induction of Th differentiation function, and B cell receptor expression pathway were significantly upregulated in B cells in GGNs compared with SNs. ^16^ In terms of the degree of infiltration, Lu et al. found a greater proportion of B cells in GGNs than in SNs, ^16^ while Kim et al. found that the proportion of B cells in nLung was also less than that in GGNs, ^29^ which appears to imply a special status of B cells in GGNs. In another study of 15 patients with GGN‐ADC and 15 patients with SADC, the results of immunohistochemistry showed that B cell abundance was not significantly different in GGN‐ADC and SADC, implying that B cells may not play a critical role in the progression of GGN‐ADC. ^25^ Because the function of certain B cell subpopulations in lung cancer immunity is unclear (e.g., Breg, granzyme‐secreting B cells), ^33^ more studies are needed to determine their role in GGN‐ADC, and it is still too early to deny the therapeutic potential of B cells.
NK cells can directly lyse tumor cells and also inhibit tumor cell growth by secreting IFN‐γ, TNF‐α, and GM‐CSF. However, in advanced lung cancer, all of the above functions of NK cells are inhibited. TGF‐β released by tumor cells downregulates the expression of activation receptors such as NKG2D and NKp30 on the surface of NK cells. ^34^ In addition, increased expression of NKG2A and decreased expression of Ki67, an inhibitory receptor on the surface of NK cells, were observed in lung cancer tissues. ^35^ Thus, it has been suggested that the tumor‐killing effect of NK cells is limited to the early stages of lung cancer. ^36^ Lu et al. found that NK cells were enriched in GGNs and exhibited upregulated Rap1, PI3K/AKT pathway and OXPHOS than that in SNs, suggesting stronger immune function of NK cells in GGNs. ^16^ Whereas, Nelson et al. found lower CD57+ expression, which was a marker of NK cell, in GGN than that in SN.37 Another study also found a trend of decreasing numbers and functions of NK cells in nLung, GGNs and SNs. ^25^ Zhang et al. found that this change in NK cells was synchronized with IL‐6 by scRNA‐seq of nLung and GGNs, and further in vitro induced culture revealed that IL‐6 did have a promotional effect on the proliferation of NK cells, and this effect was particularly evident in GGNs. ^38^ The role of combined cytokine supplementation therapies based on NK cells in NSCLC has recently been demonstrated, and approaches such as NK‐92 and chimeric antigen receptor (CAR)‐transduced NK cells are being explored in lung cancer. ^39^ Therefore, fully utilizing the antitumor function of NK cells in GGNs and preventing tumor cell‐induced decline in NK cell function may be the direction of treatment of GGNs.
As an important component of adaptive immunity, T and B cells can recognize tumor antigens through specific receptors, so TCR and B cell receptor (BCR) are also another important measure of how they work in the tumor microenvironment. A study of T cell receptor beta locus and immunoglobulin heavy‐chain gene clonal rearrangements of infiltrating T and B cells in early‐stage primary lung adenocarcinomas with different prognoses found that compared to early‐stage lung adenocarcinomas that did not recur, recurrent early stage lung adenocarcinomas TCR diversity was significantly lower, while BCR diversity was not significantly different. ^40^ In addition, peripheral blood analysis of patients with advanced lung cancer showed that advanced lung cancer had lower TCR diversity compared with normal lung tissue or early lung cancer. ^41^ , ^42^ Therefore, high TCR diversity is considered a marker of good prognosis. TCR sequencing of tumor and peripheral blood from GGN‐ADC and SADC patients by Chen et al. showed a significant decrease in TCR clonality and the proportion of TCR colonies in the top 10 amplifications in GGNs and an increase in TCR colonies in peripheral blood mononuclear cells (PMBC), compared to SNs, suggesting that GGN‐ADC patients have more diverse TCRs. ^23^ Wang et al. performed TCR tonometry in patients with AIS and early invasive adenocarcinoma (ADC) presenting with a ground‐glass shadow, and showed that TCR clonality was reduced in GGNs compared to nLung, except for Treg cells. ^43^
Macrophages are differentiated from bone marrow monocytes and are an important component of intrinsic immunity. In terms of origin, tumor‐associated macrophages (TAM) in the immune microenvironment of lung cancer can be composed of alveolar macrophages, which is known as tissue‐resident macrophages (TRM), and macrophages derived from peripheral blood adult monocytes (MDM). It has been shown that TRM promote epithelial mesenchymal transition (EMT) of tumor cells in the early stages of the tumor, whereas as the tumor progresses TRM gradually migrate to the margins of the lesion, and MDM gradually become the mainstay of advanced cancers. ^44^ Functionally, macrophages can be classified into two types, M1 and M2, which are polarized from unactivated M0 cells. M1 are classical proinflammatory macrophages, which play a direct role in killing tumor cells, while M2 exhibit anti‐inflammatory properties and are responsible for stromal remodeling and angiogenesis. ^45^ Yuan et al. cocultured subcutaneously injected M1 and M2 with the NSCLC mouse cell line A549 into NOD/SCID mice, respectively, and found that M1 induced apoptosis and reduced angiogenesis, whereas M2 significantly increased tumor volume and weight. ^46^ Further, stimulated by different cytokines, M2 is also divided into four M2a, M2b, M2c and M2d. Functionally, M2a and M2b are associated with immunomodulation, M2c inhibits immune responses and is involved in tissue remodeling, while M2d is involved in angiogenesis and tumor progression. They show protumorigenic activity and are the mainstay of TAM. ^47^ Although it has been shown that macrophages in the GGN do not express the classical marker molecules for M1 or M2, ^43^ it is still reasonable to describe their function at TIME in this way. Lu et al. have found that a higher proportion of perivascular macrophages expressing anti‐inflammatory M2 dominant genes (e.g., CD40, CSF1R, and CCL2) were found in the GGN compared to nLung, whereas more proinflammatory M1 dominant genes were expressed in macrophages in the GGNs compared to the SNs. ^16^ In terms of the degree of infiltration, both CD163+ and CD68+ TAM proportions were less in GGNs than that in SNs. ^25^ Another study comparing GGNs and lung ADC with lymph node metastasis (mLUAD) showed that macrophages expressing TAM gene were deleted in GGNs and enriched in mLUAD, ^18^ again suggesting that anti‐inflammatory M2 fine‐type macrophages were more abundant in the TIME of SNs. Given the important role of TAM in tumor progression, an approach that catalyzes the conversion of macrophages to the M1 phenotype may have therapeutic value.
The role of granulocytes in the immune microenvironment of lung cancer still needs to be proved by a large number of studies. Sarraf et al. retrospectively analyzed 1781 patients with NSCLC and found that their peripheral blood neutrophil/lymphocyte ratio (NLR) was positively correlated with higher lung cancer stage. ^48^ There is clinical evidence suggesting that eosinophilia is associated with a favorable prognosis in patients with advanced NSCLC treated with immune checkpoint inhibitors, but the mechanism by which it exerts its influence needs further investigation. ^49^ ScRNA‐seq results showed that neutrophils were enriched to a greater extent in nLung lung tissues than that in GGNs, ^17^ and eosinophils were infiltrated to a higher extent in GGNs than that in SNs. ^23^ It is difficult to see the therapeutic value of granulocytes in GGNs with these preliminary studies.
Dendritic cells include subtypes named plasma cell‐like DCs (pDC) and classical DCs (cDC). pDC play a significant role in anti‐virus immunity, and cDC are specialized antigen‐presenting cells (APCs) that exert an important influence on the activation of antitumor T cells. However, DC performing these functions are excluded from the TIME, while pDC and regulatory DCs (DCreg) with immunosuppressive properties are recruited. ^50^ Li et al. found that the proportions of all three DC subtypes were significantly higher in GGNs than that in nLung, including monocyte‐derived DC (FCGR2B+CCL17+CLEC10A+), migratory conventional DC (CCR7+LAMP3+CCL22+) and type 2 conventional DC (CD1A+CD207+HLADQB2+), and antigen presentation function of DC in GGNs was more prominent. ^17^ In contrast, the number and function of DCs in GGNs did not change significantly compared with those in SNs.
CTL and NK cells are the mainstay of tumor cell killing in the adaptive and intrinsic immune systems, respectively, by the classical mechanism of the perforin‐granzyme (or granule exocytosis) pathway (Figure 1). ^51^ However, according to the above summary, the number and function of CD8+ T cells and NK cells are reduced in GGNs compared with nLung, ^38^ , ^43^ which is attributed to the fact that their function receives influence from other immune components and tumor cells. Tumor cells upregulate heterogeneous ligands such as HLA‐C molecules, and other reasons include shedding of NKG2D ligands, and release of immunosuppressive cytokines (i.e., IL‐6, IL‐10, and TGF‐β). ^39^
FIGURE 1 Interaction of immunocytes in the tumor immune microenvironment (TIME) of ground‐glass nodules (GGNs). Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells are the main killers of tumor cells. CTL can disrupt tumor cell membranes by secreting perforin and granzyme, and also induce apoptosis through Fas/FasL, a pathway that is also seen in NK cells. In addition, NK cells can antagonize tumor cells through antibody‐dependent cell mediated cytotoxicity (ADCC). Th1 and M1 cells secrete proinflammatory cytokines to promote CTL and NK cell differentiation and inhibit tumor growth, whereas Th2 and M2 cells secrete anti‐inflammatory cytokines to inhibit CTL and NK function and aid in tumor immune escape, which can also promote angiogenesis and tumor growth. Eosinophils can recruit M1 cells to antagonize tumor progression, but its recruitment of Th2 is equally pronounced in the ground‐glass nodules (GGNs). In addition, in response to tumor‐secreted immunosuppressive factors, the number of DCreg, Treg and Breg, which are regulatory cells, was significantly upregulated, and inhibitory cytokines such as IL‐10 and TGF‐β were secreted to suppress antitumor immunity. In addition, the high expression of PD‐L1 on the surface of Breg and the high expression of PD‐L1 and CTLA‐4 indicated by Treg mediated the defective immune function of B and T cells through intercellular junctions.
As helper cells, Th1 T cells produce cytokines such as IL‐2 and IFN‐γ to exert antitumor immunity, ^52^ whereas Th2 T cells produce IL‐4, IL‐5, IL‐6, and IL‐13 while exerting tumor immune tolerance and antagonizing Th1 cell function. ^21^ , ^53^ Th2 has a greater proportion in the TIME of GGNs than it does in SNs, which implies that Th cell clusters exert a more cytotoxic cytotoxicity against CTL and NK cells’ strong inhibitory effect. In addition, Th17 cells secrete IL‐17 to promote tumor growth, migration, and immune tolerance, ^54^ but this has not been emphasized in the current GGNs. Numerous classifications of Tregs, the most representative of which is the CD4+CD25+Foxp3+ iTreg. TGF‐β and IL‐2s are indispensable for CD4+CD25+Foxp3+ iTreg development and differentiation indispensable conditions, ^55^ they secrete immunosuppressive cytokines such as TGF‐β and express high levels of cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) on the cell surface, leading to Treg‐associated immune dysfunction in patients with NSCLC. ^56^ In addition to producing antibodies to antagonize tumor cells, B cells promote the differentiation of CD4+ and CD8+ T cells. Bregs display their characteristic immunosuppression by secreting cytokines or upregulating immunomodulatory ligands (Figure 1) that attenuate T and NK cell responses and/or promote the pro‐tumorigenic effects of Tregs, MDSC, and TAM. ^57^
M1 is activated in the inflammatory milieu formed by Th1 cells, and when activated, it can produce a large number of cytokines to promote the inflammatory response, ^58^ but M1 macrophages support the initiation of tumorigenesis through the production of reactive oxygen species and nitrogen intermediates, which induce DNA damage in proliferating cells and peripheral epithelial cells, rendering them susceptible to neoplastic transformation. ^59^ , ^60^ This may explain the greater predominance of M1 in GGNs compared to SNs. As cancer progresses, tumor cells recruit monocyte precursors from the bloodstream and secrete cytokines such as IL‐4, IL‐10, and IL‐13, leading to the differentiation of monocytes into activated M2‐like TAM. M2‐like TAM releases inhibitory immune‐induced immune escape such as TGF‐β, IL‐10, and MMP‐7, which supports tumor cell proliferation, survival, epithelial‐mesenchymal transformation, invasion, and metastasis process. ^61^ , ^62^
cDC induce cellular and humoral immunity by forming MHC I/CD8 or MHC II/CD4 immunological synapses with initial T cells, while pDC produce large amounts of IFN‐γ, thereby accelerating innate and adaptive immunity and thus suppressing tumor progression ^63^ Comparatively, lung tumors also cause DC to express immunosuppressive markers and can even be reprogrammed to convert cDC into DCreg to evade immune surveillance. ^64^ , ^65^ In addition, DCreg can induce a higher proportion of Tregs to maintain immune tolerance, ^66^ which may potentially hinder tumor clearance in lung cancer TIME. Compared with SNs, dendritic cells in GGNs have low expression levels of indoleamine 2,3‐dioxygenase 1 (IDO1), a gene that inhibits T cell activation and induces T cells to differentiate into suppressor regulatory T cells, suggesting that DC function is less impaired in GGNs than in SNs. ^18^
Among granulocytes, eosinophils seem to receive extra attention, and several studies have shown that they are attracted to cytokines and chemokines secreted by tumor cells, ^67^ , ^68^ and play an inhibitory role in tumor growth in TIME. In addition, it facilitates the recruitment of NK and CTL cells to kill tumors and contributes to macrophage polarization to M1. ^69^ Among GGNs, more eosinophils than SADCs recruit more Th2 cells, making the immune environment inert. ^23^
The present study reviewed the major cellular components in the TIME of GGN‐ADC, described their roles in lung adenocarcinoma immunity, respectively, and compared their degree of infiltration and function in GGN‐ADC with that of SADC. Based on the previous description, different immune cells play their own functions and crosstalk, antagonize and cooperate with each other, forming a tight and complex microenvironment. Among them, T cells still occupy a major role in GGN‐ADC immunity, but the unsatisfactory efficacy of PD‐1/PD‐L1 inhibitors undoubtedly casts a shadow over T cell‐targeted therapy for GGN. Second, the study of NK cells and macrophages in intrinsic immunity in GGN has provided new ideas for their treatment, since both of them have been well studied in tumor immunity, targeted mechanistic studies and pharmacological agents could be developed. B cells, as the other part of adaptive immunity, are much less important than T cells in TIME of GGN, and their role in tumor immunity is not yet clear and it is not recommended as a therapeutic target for GGN‐ADC. As for granulocytes and DCs, the roles of both in GGN‐ADC at present are unclear and even the preliminary studies are limited, and their prospects are uncertain.
Conceptualization: Xiao Li. Writing‐original draft Changtai Zhao. Writing‐review and Changtai Zhao, Rongxin Xiao and Xiao Li. All the authors have read and approved the final version of the manuscript and agreed with the order of presentation of the authors.
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study.
This study was supported by National Natural Science Foundation of China (no. 92059203) and The Beijing Municipal Program Project of Collaborative Research on Major and Difficult Diseases by Integrating Traditional Chinese Medicine and Western Medicine. (2023BJSZDYNJBXTGG‐012).
Zhao C, Xiao R, Jin H, Li X. The immune microenvironment of lung adenocarcinoma featured with ground‐glass nodules. Thorac Cancer. 2024;15(19):1459–1470. 10.1111/1759-7714.15380