NK cells and CD8+ T cells cooperate to improve therapeutic responses in melanoma treated with interleukin-2 (IL-2) and CTLA-4 blockade

Abstract

BackgroundMelanoma is one of the few types of cancer with an increasing annual incidence. While a number of immunotherapies for melanoma have been associated with significant clinical benefit, including high-dose IL-2 and cytotoxic T lymphocyte antigen 4 (CTLA-4) blockade, clinical response to either of these single agents has been limited to 11-20% of treated patients. Therefore, in this study, we sought to test the hypothesis that the combination of IL-2 and CTLA-4 blockade could mediate a more profound therapeutic response.MethodsHere, B6 mice were challenged with poorly immunogenic B16 melanoma on day 0, and treated with CTLA-4 blocking antibody (100 μg/mouse) on days 3, 6, and 9, and IL-2 (100,000 units) twice daily on days 4–8, or both.ResultsA highly significant synergistic effect that delayed tumor growth and prolonged survival was demonstrated with the combination immunotherapy compared to either monotherapy alone. The therapeutic effect of combination immunotherapy was dependent on both CD8+ T and NK cells and co-depletion of these subsets (but not either one alone) abrogated the therapeutic effect. CTLA-4 blockade increased immune cell infiltration (including CD8+ T cells and NK cells) in the tumor and IL-2 reduced the proportion of highly differentiated/exhausted tumor-infiltrating NK cells.ConclusionsThese results have implications for the design of clinical trials in patients with metastatic melanoma and provide new insights into how the immune system may be mediating anti-tumor activity with combination IL-2 and CTLA-4 blockade in melanoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-015-0063-3) contains supplementary material, which is available to authorized users.

Transfer learning between preclinical models and human tumors identifies conserved NK cell activation signature in anti-CTLA-4 responsive tumors

“…A very recent study also showed that an anti-CTLA-4-EGFR immunoconjugate enhances the in vitro lysis of breast cancer cells by NK cells (Passariello et al, 2020). In B16 melanoma models, NK cells and CD8+ T cells synergistically clear tumors in response to anti-CTLA-4 and IL-2 treatment (Kohlhapp et al, 2015). Furthermore, anti-CTLA-4 has been shown to increase transcriptional markers of NK cell cytotoxic activity in CT26 colon carcinoma tumors (Sanseviero et al, 2019).…”

Increases in Absolute Lymphocytes and Circulating CD4+ and CD8+ T Cells Are Associated with Positive Clinical Outcome of Melanoma Patients Treated with Ipilimumab

“…In mice, efficacy of ipilimumab and IL2 in combination was dependent on both CD8 + T and NK cells. Codepletion of these subsets (but not either one alone) abrogated the therapeutic effect (38). Ipilimumab has been shown to trigger antibody dependent cellular cytotoxicity (ADCC) of CTLA-4–expressing melanoma cell lines through TNFα release by CD16 + NK cells (39) and can mediate lysis of Tregs via CD16 + nonclassical monocytes (40).…”

Syngeneic Syrian hamster tumors feature tumor-infiltrating lymphocytes allowing adoptive cell therapy enhanced by oncolytic adenovirus in a replication permissive setting

“…The role of NK cells in TIL products is unclear, but could prove valuable as shown in murine B16 melanoma, where the depletion of NK cells and CD8 C T cells together (but not either alone) abrogated the therapeutic efficacy of high-dose IL-2 and CTLA-4 blockade. 33 Similarly, the importance of CD4 C T cells in TIL products remains poorly understood since some patients have responded well to TIL treatments dominated by CD4 C T cells. 32 Preclinically, cotreatment with tumor-specific CD4…”