Immunotherapy and Targeting the Tumor Microenvironment: Current Place and New Insights in Primary Pulmonary NUT Carcinoma

Abstract

Primary pulmonary nuclear protein of testis carcinoma is a rare and highly aggressive malignant tumor. It accounts for approximately 0.22% of primary thoracic tumors and is little known, so it is often misdiagnosed as pulmonary squamous cell carcinoma. No effective treatment has been formed yet, and the prognosis is extremely poor. This review aims to summarize the etiology, pathogenesis, diagnosis, treatment, and prognosis of primary pulmonary nuclear protein of testis carcinoma in order to better recognize it and discuss the current and innovative strategies to overcome it. With the increasing importance of cancer immunotherapy and tumor microenvironment, the review also discusses whether immunotherapy and targeting the tumor microenvironment can improve the prognosis of primary pulmonary nuclear protein of testis carcinoma and possible treatment strategies. We reviewed and summarized the clinicopathological features of all patients with primary pulmonary nuclear protein of testis carcinoma who received immunotherapy, including initial misdiagnosis, disease stage, immunohistochemical markers related to tumor neovascularization, and biomarkers related to immunotherapy, such as PD-L1 (programmed death-ligand 1) and TMB (tumor mutational burden). In the meanwhile, we summarized and analyzed the progression-free survival (PFS) and the overall survival (OS) of patients with primary pulmonary nuclear protein of testis carcinoma treated with PD-1 (programmed cell death protein 1)/PD-L1 inhibitors and explored potential population that may benefit from immunotherapy. To the best of our knowledge, this is the first review on the exploration of the tumor microenvironment and immunotherapy effectiveness in primary pulmonary nuclear protein of testis carcinoma.

Keywords: NUT carcinoma; immune checkpoint inhibitor; immunotherapy; midline carcinoma; nuclear protein of testis carcinoma; pulmonary; tumor microenvironment.

Figure 1

Pathogenesis of NUT carcinoma. (A) BRD4-NUT fusion oncoprotein binds to histone acetylated lysine residues in chromatin and recruits the histone acetyltransferase (HAT) p300. HAT p300 makes adjacent histones acetylated, which allows more BRD4-NUT fusion oncoproteins to bind to chromatin and recruit transcription factors to form transcription complex. The transcription complex is sequestered to regions of the chromatin that transcribe pro-proliferative and anti-differentiation genes, such as MYC, TP63, SOX. While it leads to the silencing of differentiation genes, thereby repressing differentiation and promoting proliferation. (B) With the use of BETi or HAT p300 inhibitor can induce differentiation and inhibit proliferation.

Figure 2

Imaging characteristics of chest CT. (A, B) The mass is located in the right upper lobe and is of central type with moderate to large pleural effusion on the right (arrow: mass, triangle: pleural effusion). (C, D) They show the ipsilateral pleural nodule but no involvement of the contralateral lung (arrow:pleural nodule). (E) Contralateral mediastinal lymphadenopathy. (F) Ipsilateral hilar lymphadenopathy.

Figure 3

Pathological features of NUT carcinoma. (A, B): The tumor cells are nested or sheet-like arrangement (white arrow). The nuclei are large and hyperchromatic. Tumor cells of squamous epithelial differentiation can be seen (black arrow). (C, D) (H&E staining): The tumor is poorly differentiated and shows infiltrative growth. The tumor cells are irregular nest-like, polygonal, large nucleus and heteromorphic. There are abrupt squamous epithelial differentiation and keratinized bead (arrow). (E) (IHC): CK5/6 (+) (F) (FISH): Dual-color split probes targeting both sides of the NUT gene breakpoint are seperated (oval).

Figure 4

The main mechanism of PD-1 or PD-L1 inhibitors. (A) PD-1 is expressed on the surface of T cells. Its ligands are PD-L1 or PD-L2 on the surface of tumor cells and PD-L1 on the surface of antigen-presenting cells (APCs). The combination of PD-1 and its ligand inhibits the activation of T cells, leading to immune escape of tumor cells. (B) PD-1 or PD-L1 inhibitors block the binding of PD-1 to its ligands and restore the immune killing of tumor cells.

Figure 5

The main mechanisms of combination therapy with PD-1/PD-L1 inhibitors. (A) Radition results in tumor cell death. Tumor-associated antigens (TAAs) are released and antigen-presenting cell is activated. CD8+ T cell is then primed by binding to APC. (B) VEGF stimulates angiogenesis, promotes the infiltration of T regulatory cell (Treg), decreases TIL infiltration and promotes the formation of T exhausted cell (Tex). (C) Tumor-derived IL-8 can promote tumor angiogenesis and recruit MDSC to suppress anti-tumor immune responses.