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.

Effects of KRAS, STK11, KEAP1, and TP53 mutations on the clinical outcomes of immune checkpoint inhibitors among patients with lung adenocarcinoma

“…In our study, although a significant association between the gene status and treatment response of any of the evaluated patients was not observed, KEAP1 mutation contributed to an inferior OS, which supported the findings of a previous report indicating that KEAP1 mutation is a prognostic factor for patients with lung adenocarcinoma receiving ICIs. Although the effect of TP53 on the OS of patients treated with ICIs remains controversial [ 5 , 11 , 21 ], our results indicated a negative prognostic role for TP53 mutation, which was consistent with the role of TP53 in immune evasion through the regulation of immune checkpoint expression [ 22 ].…”

“…However, compared to single mutations of KRAS , KRAS and TP53 , comutations were more strongly associated with PD-L1 positivity, which was consistent with the findings of a previous study [ 13 ]. On the other hand, we reported similar results showing that STK11 , KEAP1 and TP53 mutations were associated with an increased TMB [ 5 , 25 ]. Generally, an increased TMB is associated with longer survival in cancer patients receiving ICIs [ 27 ].…”

“…Alterations in several tumor genes, such as mutations in KRAS , STK11 , and KEAP1 , have been suggested as potential biomarkers for the ICI response in patients with NSCLC [ 5 ]. KRAS mutations are the most common clonal oncogenic driver in NSCLC and are present in 35% of lung adenocarcinomas [ 6 ].…”

“…TP53 encodes the p53 tumor suppressor protein, a master regulator of the cell cycle and cell death [ 10 ]. TP53 mutations were found in approximately 42% of patients with KRAS -mutant NSCLC, and comutation with KRAS was linked to an inflammatory tumor microenvironment [ 5 , 11 ]. Moreover, KRAS mutation can upregulate NRF2 signal transduction, contributing to oncogenic transformation and senescence evasion [ 12 ].…”