Cancer Cell-Intrinsic Alterations Associated with an Immunosuppressive Tumor Microenvironment and Resistance to Immunotherapy in Lung Cancer

Abstract

Despite the great clinical success of immunotherapy in lung cancer patients, only a small percentage of them (<40%) will benefit from this therapy alone or combined with other strategies. Cancer cell-intrinsic and cell-extrinsic mechanisms have been associated with a lack of response to immunotherapy. The present study is focused on cancer cell-intrinsic genetic, epigenetic, transcriptomic and metabolic alterations that reshape the tumor microenvironment (TME) and determine response or refractoriness to immune checkpoint inhibitors (ICIs). Mutations in KRAS, SKT11(LKB1), KEAP1 and TP53 and co-mutations of these genes are the main determinants of ICI response in non-small-cell lung cancer (NSCLC) patients. Recent insights into metabolic changes in cancer cells that impose restrictions on cytotoxic T cells and the efficacy of ICIs indicate that targeting such metabolic restrictions may favor therapeutic responses. Other emerging pathways for therapeutic interventions include epigenetic modulators and DNA damage repair (DDR) pathways, especially in small-cell lung cancer (SCLC). Therefore, the many potential pathways for enhancing the effect of ICIs suggest that, in a few years, we will have much more personalized medicine for lung cancer patients treated with immunotherapy. Such strategies could include vaccines and chimeric antigen receptor (CAR) cells.

Keywords: cancer cell-intrinsic; gene mutations; immunotherapy resistance; lung cancer.

Figure 1

Effect of STK11 and KEAP1 mutations on some key cancer cell intracellular pathways and the TME, compared to wild-type tumors. The STK11 mutation blocks phosphorylation of AMP-activated protein kinase (AMPK) and promotes serine utilization and synthesis of S-adenosyl methionine (SAM), which is a substrate for several epigenetic silencing enzymes, like DNMT1 and EZH2. This, in turn, causes the silencing of STING (STimulator of INterferon Genes). These and other alterations lead to an immunosuppressive TME. KEAP1 functions as an adaptor protein for Cullin3, an E3 ligase that negatively regulates NRF2 activity. KEAP1 binding to NRF2 causes proteasomal degradation of NRF2. The KEAP1 mutation allows NRF2 to aberrantly bind antioxidant response elements (ARE) and turn on the transcription of genes related to anti-redox activity, ROS detoxification, NADPH regeneration and iron metabolism. NRF2 hyperactivity also alters numerous metabolic-related pathways that, ultimately, affect the activity of immune cells within the TME and cause a lack of response to ICIs. Created with BioRender.

Figure 2

Some of the key modulators of the TME in SCLC and possible therapeutic strategies to overcome resistance to ICIs. SCLC subtypes are characterized by expression of ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P) or YAP1 (SCLC-Y). A novel subtype, SCLC-I, was defined by an inflamed gene signature that included immune checkpoint molecules (PD-L1, PD-1, CTLA-4, TIGIT, VISTA, ICOS, LAG3), genes encoding HLAs and chemokines CCL5 and CXCL10. These tumors are particularly sensitive to anti-PD-1 therapy. In the other subtypes, which are in general refractory to immunotherapy alone, different strategies have been proposed to enhance immunogenicity: (a) rovalpituzumabtesirine (Rova-T) to block the Notch ligand DLL3; (b) use of DNA damage agents, such as radiotherapy or PARP inhibitors, which increase levels of CXCL10, CCL5 and Type I IFN, and recruit cytotoxic T cells; (c) increase the expression of MHC-I, which may be downregulated by lysine-specific demethylase 1a (LSD1)-driven epigenetic silencing. Inhibition of LSD1 (for instance, with bomedemstatin) restores MHC-I expression, activates IFN signaling and induces immune activation; (d) CDK7 is a master regulator of cell-cycle progression in SCLC. CDK7 blockade impairs DNA replication and the cell cycle, causing replicative stress and activation of an immune response. The CDK7-inhibitor YKL-5-124 increases pro-inflammatory cytokines and chemokine production. Created with BioRender.