Targeting immune cell types of tumor microenvironment to overcome resistance to PD-1/PD-L1 blockade in lung cancer

Abstract

Lung cancer is the common malignant tumor with the highest mortality rate. Lung cancer patients have achieved benefits from immunotherapy, including immune checkpoint inhibitors (ICIs) therapy. Unfortunately, cancer patients acquire adaptive immune resistance, leading to poor prognosis. Tumor microenvironment (TME) has been demonstrated to play a critical role in participating in acquired adaptive immune resistance. TME is associated with molecular heterogeneity of immunotherapy efficacy in lung cancer. In this article, we discuss how immune cell types of TME are correlated with immunotherapy in lung cancer. Moreover, we describe the efficacy of immunotherapy in driven gene mutations in lung cancer, including KRAS, TP53, EGFR, ALK, ROS1, KEAP1, ZFHX3, PTCH1, PAK7, UBE3A, TNF-α, NOTCH, LRP1B, FBXW7, and STK11. We also emphasize that modulation of immune cell types of TME could be a promising strategy for improving adaptive immune resistance in lung cancer.

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

“…The clinical benefit of PD-1/PD-L1 in patients with EGFR -mutated tumors is minimal, but the type of mutation seems to have a different impact on the outcome: the presence of the L858R mutation, exon 19 deletions or the T790M resistant mutation seem to play a role in the response to ICIs [ 58 , 59 ]. Immunosuppressive effects of EGFR mutations involve an increase in Tregs, MDSCs and tumor-associated macrophages (TAMs), as well as lower numbers of CD8+ T cells [ 60 , 61 ]. Tumor infiltration of Tregs is favored by indoleamine 2, 3-dioxygenase (IDO) production by DCs, which promotes Tregs conversion [ 59 ].…”

“…In EGFR -defective tumors, an upregulation of immunoglobulin-like transcript 4 (ILT4) has been described. This leads to increased M2 polarization and impairment of T-cell proliferation and cytotoxicity [ 60 , 62 ]. ILT4 inhibition promoted anti-PD-L1 efficacy, followed by a decrease in TAMs and Tregs [ 60 , 62 ].…”

“…This leads to increased M2 polarization and impairment of T-cell proliferation and cytotoxicity [ 60 , 62 ]. ILT4 inhibition promoted anti-PD-L1 efficacy, followed by a decrease in TAMs and Tregs [ 60 , 62 ]. EGFR-Tyrosine Kinase Inhibitors (TKIs) may synergize with ICIs due to the upregulation of MHC classes I and II, suppression of Tregs and decrease in PD-L1 expression [ 60 ].…”

“…ILT4 inhibition promoted anti-PD-L1 efficacy, followed by a decrease in TAMs and Tregs [ 60 , 62 ]. EGFR-Tyrosine Kinase Inhibitors (TKIs) may synergize with ICIs due to the upregulation of MHC classes I and II, suppression of Tregs and decrease in PD-L1 expression [ 60 ]. The combination of TKIs with immunotherapies is being tested in phase I trials and includes the use of Nivolumab (NCT01454102), Pembrolizumab (NCT02039674) and Atezolizumab (NCT02013219) [ 63 ].…”

“…Mutations in other genes have also been associated with a particular modification of the TME and, in some cases, with immunotherapy response/refractoriness. Those include ALK , ROS1 , ZFHX3 , PTCH1 , PAK7 , UBE3A , TNF-α , LRP1B and FBXW7 [ 60 ]. However, more studies are needed to clarify their implication in ICI response.…”