Pathology, immunosuppression and NK cell immunotherapy of non-small cell lung cancer

Lung cancer is one of the leading causes of cancer incidence and mortality. Non-small lung cancer (NSCLC) makes up almost 80 % of lung cancer cases. Treatments for NSCLC have traditionally been restricted to surgeries, radiotherapy, and chemotherapy. However, despite these therapies being able to induce remission in a proportion of patients, many lung cancer patients experience tumor recurrence. To combat high relapse rates, the adoptive transfer of natural killer (NK) cells as NSCLC immunotherapy is attractive as these cells do not require antigen presentation, do not induce GvHD, and can be active in allogeneic settings. However, NSCLC response rates remain low because of the development of resistance mechanisms to NK cell attack. Much of the resistance stems from metabolic reprogramming occurring in the lung cancer tumor microenvironment, owing to aggressive metabolic activity of cancer cells resulting in the production of immunosuppressive metabolites and metabolic byproducts, including oncometabolites. Immune evasion via MHC loss and malignant transformation toward an immunosuppressive niche alters NK cell chemotaxis, reduces their recruitment and impairs their activation. Here, we discuss NSCLC pathophysiology, the immune crosstalk in the NSCLC TME, as well as how the TME, particularly oncometabolite-mediated immunosuppression, metabolic reprogramming and immune dysfunction regulates therapeutic responses and NK cell functional alterations in NSCLC to ultimately drives response resistance.