Excerpt
Small cell lung cancer (SCLC) represents an aggressive condition with no therapeutic options inducing long-lasting responses [
1]. Patients who have undergone two or more previous lines of therapy for SCLC are often symptomatic from progression of cancer, side effects of previous therapy, and comorbidities [
1]. Patients affected by SCLC who have progressed despite multiple lines of management have few therapeutic possibilities in the third line and beyond [
1]. Recently, early reports from studies with immune checkpoint inhibitors have demonstrated encouraging results with the potential for long term disease control in a subset of SCLC patients [
2]. Blockade of programmed death receptor-1 (PD-1)/programmed death ligand 1 (PD-L1) axis has been proposed as a promising treatment for metastatic SCLC beyond the frontline [
2]. PD-L1 expression status of tumor cells is usually utilized to select patients who might be more likely to benefit from immune checkpoint inhibitors [
2]. SCLC tumor cells have been suggested to modulate responses of CD4(+) T cells from healthy donors [
3]. The CD4+ T lymphocytes have a critical role in anti-tumor immune responses [
3]. The CD4+ T cell subset include regulatory T (Treg) cells [
4]. There are two broad Treg subsets that show the transcription factor forkhead box protein P3(FOXP3) [
3]. FOXP3-expressing T regulatory cells (Tregs) are divided in naturally occurring Tregs (nTregs) and induced Tregs (iTregs) that differentiate in peripheral tissues upon exposure to Ag in a tolerogenic environment [
4]. Helios, an Ikaros family transcription factor, has been linked to transcription factor FOXP3 expression [
4]. Expression of Helios, has been proposed to specifically identify nTregs, allowing specific tracking of Tregs from different origins in health and disease [
4]. It has been reported that Helios+ and Helios
_ cells coexist within the natural FOXP3 + T Regulatory Cell Subset in Humans [
4]. Helios-nTreg clones have been found to show a suppressive capacity, as well as expression of FOXP3 and cell surface proteins similar to Helios+ nTreg clones, with the notable exception of higher production of IFNɣ [
4]. Some SCLC tumor cell lines have been connected with de novo differentiation of functional CD4(+)CD25(+)FOXP3(+)CD127
(lo)Helios(−) regulatory T (Treg) cells in healthy blood lymphocytes [
3]. Increased evidence has suggested that IFN-γ can act to promote tumor progression [
5]. It has been observed that IFN-ɣ can promote tumor cells to evade immune surveillance [
5]. It has been proved that that lung cancer cells cultured with supernatant of tumor-associated macrophages induce the expression of PD-L1 by the secretion of IFN-γ [
5]. PD-L1 induced by IFN-γ from tumor-associated macrophages has been linked to progression of lung cancer [
5]. Taken together, I hypothesize that SCLC cells may lead to increased expression of PD-L1 through up-regulation of IFN-γ by increasing differentiation of Helios- cells. For that reason, I suppose that the potential of an interaction between PD-L1 and IFN-ɣ axis via Helios- cells in SCLC progression may represent a warranted reason for using PD-L1/PD-1 inhibitors in SCLC management. Further research is needed for selecting appropriate patient subpopulations for clinical trials. …
