Unraveling the immune mechanisms and therapeutic targets in lung adenosquamous transformation

Abstract

Adenocarcinoma-to-squamous cell carcinoma transformation (AST) induces drug resistance in patients with lung adenocarcinoma (LUAD), often resulting in unfavorable clinical outcomes. In recent years, it has been found that alterations in the tumor immune microenvironment (TIME) during adenosquamous carcinoma trans-differentiation also influence the efficacy of immunotherapy. Moreover, the aberrant expression and activation of several driver genes for AST lead to abnormal infiltration and function of immune cell by remodeling the cellular inflammatory phenotype. In this review, we will systematically present the changes in the TIME and molecular regulatory mechanisms during adenosquamous carcinoma differentiation, aiming to gain a better understand of the function of immune cells during this process and the potential value of combining immunotherapy to enhance the treatment of non-small cell lung cancer (NSCLC).

Keywords: adenocarcinoma-to-squamous cell carcinoma transformation (AST); adenosquamous lung carcinoma (ASLC); tumor immune microenvironment (TIME); tumor-associated macrophages (TAMs); tumor-associated neutrophils (TANs).

Figure 1

(1) The EML4-ALK fusion protein produced by ALK rearrangement can activate the JAK-STAT signaling pathway. The activated JAK-STAT signaling plays an important promoting role in the process of AST; (2) TET2 promotes neutrophil lipid transfer through STAT3-mediated CXCL5 expression, thus facilitating the process of AST; (3) In KRAS-mutated lung cancer with LKB1 deficiency, the AMPK-FAO pathway is disrupted by the excessively accumulated ROS. Meanwhile, ROS mediates the shutdown of the Wnt/β-catenin signaling pathway through FOXO3A, disrupting the balance of the TF network,thus promoting the development of AST; (4) The upstream TFs of ASLC form a regulatory network centered around NKX2-1, FOXA2, SOX2 and TP63; (5) In KRAS-driven LUAD, SOX2 promotes the recruitment and infiltration of TANs through CXCL3 and CXCL5; (6) YAP inhibits ASLC with LKB1 deficiency by suppressing DNp63 mediated by ZEB2; (7) Activation of the PI3K/AKT pathway can induce squamous characteristics in an EGFR-mutated LUAD model; (8) The deletion of FOXA1and the overexpression of FOXM1synergistically drive AST (63); (9) The knockout of FOXA1 significantly upregulates the transcription of DNp63 in tumor cells. The protein level of FOXA1 is downregulated in tumors with DNp63 overexpression, while it is upregulated in tumors with DNp63 knockout. TFs, transcription factors; LUSC, lung squamous cell carcinoma; LUAD, lung adenocarcinoma; ASLC, adeno-squamous lung carcinoma; TANs, tumor-associated neutrophils; AST, adeno-squamous transformation.

Figure 2

(1) Treatment with EGFR-TKI or KRAS inhibitors may lead to AST. For patients with STK11/LKB1 mutations, the KRT6A gene is highly expressed in the AST transitional state. Under the influence of the local TME, M2-TAMs affects LSD1 and indirectly promotes the tumor cell proliferation and invasion process mediated by KRT6A, affecting treatment prognosis; (2) Tumor cells can induce neutrophils through TGFβ1 to promote EMT. In KRAS-driven LUAD, there is recruitment and infiltration of TANs mediated by CXCL3 and CXCL5. TET2 promotes neutrophil lipid transfer via STAT3-mediated CXCL5 expression. TANs inhibit T cell proliferation and reduce the secretion of IFN-γ and TNF-α, affecting the TIME and promoting the AST process; (3) IL-6/IL-17 indirectly influences the TIME of AST through the JAK-STAT signaling pathway, negatively regulating neutrophils, natural killer cells, effector T cells and dendritic cells, and positively regulating regulatory T cells and MDSCs. AST, adenosquamous transformation; M2-TAMs, M2 macrophages; TANs, tumor-associated neutrophils; TIME, tumor immune microenvironment; ADCC, antibody-dependent cell-mediated cytotoxicity; ASLC, adenosquamous lung carcinoma; LUAD, lung adenocarcinoma; EMT, Epithelial-Mesenchymal Transition. Use the website "https://www.figdraw.com/#/" for drawing.

Figure 3

(1) Recruited by the chemokine signals of CCL-2 and CXCL-12, monocytes enter the TME and differentiate into macrophages under the influence of cytokines such as M-CSF and TGF-β; (2) Macrophages are subsequently stimulated by more cytokines in the TME and differentiate into two phenotypes, M1 and M2; (3) When the TME changes or under therapeutic intervention, TAMs can transform into each other; (4) Inflammatory stimulation induced by TNF-α can increase the expression of LSD1 in M2-TAM; LSD1 generates H₂O₂ and inhibits CAT, thereby promoting M1 polarization and reducing the expression of LSD1; (5) In the inflammatory subtype of ASLC, immune infiltration increases, and CCL2 promotes the migration and infiltration of macrophages at the site of inflammation. H₂O₂, hydrogen peroxide; CAT, catalase; TAMs, tumor-associated macrophages. Use the website "https://www.figdraw.com/#/" for drawing.