A 63-year-old man comes to the clinic after noticing a reddish tinge to his urine. During evaluation for hematuria, an abdominal CT scan reveals a mass in his left kidney. Further work-up shows multiple lung and bone nodules. CT-guided biopsy of a peripherally located lung nodule demonstrates renal cell carcinoma. High-dose interleukin-2 (IL-2) treatment is started, and 4 weeks later there is a significant reduction in the patient's tumor burden. Which of the following mechanisms was most likely responsible for regression of this patient's malignancy?
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Interleukin-2 (IL-2) is a cytokine produced endogenously by activated CD4 cells, CD8 cells, and natural killer (NK) cells. High-dose IL-2 infusions can also be administered to patients with advanced renal cell carcinoma or metastatic melanoma in order to increase antitumor lymphocyte activity, as follows:
CD4 cells: IL-2 converts activated CD4 cells into type 1 T-helper cells, which then secrete inflammatory cytokines (eg, IFN-gamma, TNF-alpha, IL-2) that drive an antitumor response.
CD8 cells: IL-2 expands the pool of activated CD8 cells and increases their cytotoxic killing with granzymes and perforins.
NK cells: IL-2 triggers proliferation of NK cells and dramatically increases their cytotoxic activity; most of the antitumor effect of IL-2 therapy comes from increased NK cell activity.
Although patients with advanced renal cell carcinoma who undergo IL-2 therapy may enter long-lasting remission, high-dose IL-2 treatment is nonspecific and causes significant adverse effects due to excessive cytokine production (eg, capillary leak syndrome). Therefore, most patients are now treated with newer immunotherapy agents such as CTLA-4 inhibitors (eg, ipilimumab) or PD-1 protein inhibitors (eg, nivolumab) that deliver more targeted therapy and are better tolerated.
(Choice A) Tumor hypoxia and lactic acid production increase release of vascular endothelial growth factor (VEGF), which promotes angiogenesis required for tumor growth. Therefore, anti-VEGF immunotherapy (eg, bevacizumab) can induce a potent antitumor response; it is often used for lung and colorectal cancer.
(Choice B) Although CD8 and NK cells induce cell death via apoptosis, this effect is not mediated by direct binding of IL-2 to the tumor cell. Certain chemotherapy drugs (eg, etoposide, vincristine, cyclophosphamide) directly induce apoptosis by damaging tumor cell DNA, the cytoskeleton, or mitochondria.
(Choice C) Monoclonal antibodies that target specific cell surface molecules on the tumor can induce tumor cell death via antibody-dependent cellular cytotoxicity. An example of this type of immunotherapy is alemtuzumab, a drug for chronic lymphocytic leukemia that targets a cell surface receptor (CD52) found primarily on mature lymphocytes. However, IL-2 does not directly interact with the Fc receptor on cytotoxic cells.
(Choice E) Although IL-2 triggers CD8 cells to increase expression of the inhibitory receptor PD-1 (programmed cell death protein 1), engagement of this receptor leads to T-cell exhaustion, not increased antitumor activity.
Educational objective:
Interleukin-2 (IL-2) is endogenously produced by CD4 cells, CD8 cells, and natural killer (NK) cells and has strong proinflammatory and some anti-inflammatory effects. High-dose IL-2 therapy can be used for advanced renal cell carcinoma and metastatic melanoma; this can lead to long-lasting remission due to increased cytotoxic activity of NK cells against the tumor.