Neuroendocrine subtypes of small cell lung cancer differ in terms of immune microenvironment and checkpoint molecule distribution

Abstract

Small cell lung cancer (SCLC) has recently been subcategorized into neuroendocrine (NE)‐high and NE‐low subtypes showing ‘immune desert’ and ‘immune oasis’ phenotypes, respectively. Here, we aimed to characterize the tumor microenvironment according to immune checkpoints and NE subtypes in human SCLC tissue samples at the protein level. In this cross‐sectional study, we included 32 primary tumors and matched lymph node (LN) metastases of resected early‐stage, histologically confirmed SCLC patients, which were previously clustered into NE subtypes using NE‐associated key RNA genes. Immunohistochemistry (IHC) was performed on formalin‐fixed paraffin‐embedded TMAs with antibodies against CD45, CD3, CD8, MHCII, TIM3, immune checkpoint poliovirus receptor (PVR), and indoleamine 2,3‐dioxygenase (IDO). The stroma was significantly more infiltrated by immune cells both in primary tumors and in LN metastases compared to tumor nests. Immune cell (CD45+ cell) density was significantly higher in tumor nests (P = 0.019), with increased CD8+ effector T‐cell infiltration (P = 0.003) in NE‐low vs NE‐high tumors. The expression of IDO was confirmed on stromal and endothelial cells and was positively correlated with higher immune cell density both in primary tumors and in LN metastases, regardless of the NE pattern. Expression of IDO and PVR in tumor nests was significantly higher in NE‐low primary tumors (vs NE‐high, P < 0.05). We also found significantly higher MHC II expression by malignant cells in NE‐low (vs NE‐high, P = 0.004) tumors. TIM3 expression was significantly increased in NE‐low (vs NE‐high, P < 0.05) tumors and in LN metastases (vs primary tumors, P < 0.05). To our knowledge, this is the first human study that demonstrates in situ that NE‐low SCLCs are associated with increased immune cell infiltration compared to NE‐high tumors. PVR, IDO, MHCII, and TIM3 are emerging checkpoints in SCLC, with increased expression in the NE‐low subtype, providing key insight for further prospective studies on potential biomarkers and targets for SCLC immunotherapies.

Molecular profiles of small cell lung cancer subtypes: Therapeutic implications

“…36 This categorization has major clinical impact, as the two phenotypes are anticipated to respond differently to targeted therapeutics and ICIs. 37,38 Of note, another example of NE heterogeneity was described by Gazdar et al 39,40 in 1985 based on the in vitro and in vivo behavior of SCLC cells. The "classic" phenotype is associated with typical morphology, high expression of NE markers, and non-adherent growth pattern in cell cultures.…”

“…NE-high tumors with the immune desert phenotype are associated with decreased immune cell (CD8 + effector T cells primarily) infiltration compared to NE-low tumors. 36,38 Expressions of indoleamine 2,3-dioxygenase (IDO) and poliovirus receptor (PVR), which are both important factors of the SCLC immune microenvironment, are also significantly lower in NE-high tumors (versus NE-low tumors). 38,[83][84][85] In addition, these tumors are associated with low T cell immunoglobulin and mucin domain-3 (TIM3) levels as well.…”

Construction of the optimization prognostic model based on differentially expressed immune genes of lung adenocarcinoma

“…Current studies have found that the development of cancer are not only dependent on tumor cell characteristics but are also affected by the interaction with infiltrated immunocytes [ 30 , 31 ]. The tumors with higher immune cells and mediators proportion were proved to be more effective to the immune treatment [ 32 ].…”

Beneficial Immunomodulatory Effects of Fluticasone Propionate in Chlamydia pneumoniae-Infected Mice

“…IDO activity is a hallmark of tryptophan depletion and suppression of Chlamydia growth in cell cultures and mice. Furthermore, IDO activity is associated with several pulmonary diseases, including lung cancer [ 37 ]. Sputum IDO activity was enhanced in an IL-10 dependent manner in asthmatic patients receiving ICSs; the ICSs increased IL-10 secretion from macrophages in parallel with IDO activity, indicating that ICS use could generate IDO activity through IL-10 production [ 38 ].…”