Immunological effect of tyrosine kinase inhibitors on the tumor immune environment in non‑small cell lung cancer (Review)

Abstract

Acquired resistance to tyrosine kinase inhibitors (TKIs) limits the duration of antitumor effects and impairs the survival of patients with oncogene-driven non-small cell lung cancer (NSCLC). At present, little is known about the immunomodulatory ability of TKIs during the entire treatment period, including the drug-sensitive and drug-resistant periods. The present review aimed to comprehensively explore the dynamic changes in the tumor microenvironment (TME) during TKI treatment in NSCLC. Previous clinical and preclinical studies from medical and health databases related to NSCLC are reviewed. During the response period, cytotoxic immune cells accumulate in the TME and contribute to the formation of an inflammatory microenvironment. During the resistance period, the number of immunosuppressive cells increases, as does the expression of immune checkpoint proteins, which are critical mechanisms for tumor progression. The combination of targeted therapy and immunotherapy has been explored in multiple studies, and preliminary data showed controversial results. Extensive studies are needed to confirm the criteria of the selected patient subgroups and the toxicity profiles of EGFR TKIs and immune checkpoint inhibitors (ICIs). At present, the reagents targeting other immune cells, cytokines and related pathways remain underexplored compared with the revolutionary effect of ICIs in lung cancer. In the future, the precisely selected regimens for combination treatment should be further investigated in carefully designed xenograft models and clinical trials.

Use of Systemic Therapies for Treatment of Psoriasis in Patients with a History of Treated Solid Tumours: Inference-Based Guidance from a Multidisciplinary Expert Panel

“…kinase or VEGF-targeting angiogenesis inhibitors) Most of these therapies are not expected to have significant effects on immune deficits and/or immune reconstitution. Some kinase inhibitors can cause neutropenia and are taken daily for years [ 131 , 132 ] CTLA4 cytotoxic T-lymphocyte-associated antigen 4, ICI Immune checkpoint inhibitor, PD1 programmed cell death 1, PDL1 programmed cell death ligand 1, VEGF vascular endothelial growth factor a In the setting of non-curative/palliative chemotherapy, patients may have some permanent immune suppression related to the chronic malignancy itself, receipt of multiple lines of chemotherapy, and long-term palliative use of corticosteroids, with cumulative effects on neutrophils and neutrophil recovery (more suppression, longer time to recovery, and sometimes long-lasting modest neutropenia). Further, patients may have had palliative radiation therapy, and if a larger extent of their marrow is in the radiation field, the myelosuppression/neutropenia from chemotherapy may be more severe and long lasting [ 133 ] b Some reports indicate that it could take up to 1 year for cluster of differentiation 4 (CD4) + T cells to recover.…”

CheckMate-722: The Rise and Fall of Nivolumab with Chemotherapy in TKI-Refractory EGFR-Mutant NSCLC

“…The uninflamed TME inherent to EGFR-mutant NSCLC, in conjunction with the immunosuppressive environment created as TKI resistance develops, may then explain the poor response to ICIs seen in TKI-resistant EGFR-mutant NSCLC. 29 …”

“…The uninflamed TME inherent to EGFRmutant NSCLC, in conjunction with the immunosuppressive environment created as TKI resistance develops, may then explain the poor response to ICIs seen in TKI-resistant EGFR-mutant NSCLC. 29 The immunosuppressive TME associated with EGFR-mutant NSCLC and its implications for response to immunotherapy may suggest the possibility of clinical benefit from immunotherapy used in combination with treatment modalities with immunomodulatory effects, like those targeting vascular endothelial growth factors (VEGFs). VEGFs are known to mediate the proliferation of tumor microvasculature, allowing for tumor growth and spread.…”

State-of-the-Art Molecular Oncology of Lung Cancer in Taiwan

“…In addition, immunotherapy plus chemotherapy tended to be more effective than immunotherapy alone in previously TKI-treated NSCLC harboring EGFR mutations [39]. A study showed that the level of immunosuppressive cells and immune checkpoint proteins increases during the EGFR-TKI resistance period, implicating a critical mechanism for tumor progression [40]. The decreased infiltration levels of CD8 + T cells after the development of EGFR-TKI resistance have also been reported [41].…”