Anti–CTLA-4 Activates Intratumoral NK Cells and Combined with IL15/IL15Rα Complexes Enhances Tumor Control

Abstract

Antibodies targeting CTLA-4 induce durable responses in some patients with melanoma and are being tested in a variety of human cancers. However, these therapies are ineffective for a majority of patients across tumor types. Further understanding the immune alterations induced by these therapies may enable the development of novel strategies to enhance tumor control and biomarkers to identify patients most likely to respond. In several murine models, including colon26, MC38, CT26, and B16 tumors cotreated with GVAX, anti-CTLA-4 efficacy depends on interactions between the Fc region of CTLA-4 antibodies and Fc receptors (FcR). Anti-CTLA-4 binding to FcRs has been linked to depletion of intratumoral T regulatory cells (Treg). In agreement with previous studies, we found that Tregs infiltrating CT26, B16-F1, and autochthonous Braf V600E Pten À/À melanoma tumors had higher expression of surface CTLA-4 (sCTLA-4) than other T-cell subsets, and anti-CTLA-4 treatment led to FcR-dependent depletion of Tregs infiltrating CT26 tumors. This Treg depletion coincided with activation and degranulation of intratumoral natural killer cells. Similarly, in non-small cell lung cancer (NSCLC) and melanoma patient-derived tumor tissue, Tregs had higher sCTLA-4 expression than other intratumoral T-cell subsets, and Tregs infiltrating NSCLC expressed more sCTLA-4 than circulating Tregs. Patients with cutaneous melanoma who benefited from ipilimumab, a mAb targeting CTLA-4, had higher intratumoral CD56 expression, compared with patients who received little to no benefit from this therapy. Furthermore, using the murine CT26 model we found that combination therapy with anti-CTLA-4 plus IL15/IL15Ra complexes enhanced tumor control compared with either monotherapy.

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

“…2F). These data support recent findings that NK cells within mouse tumors can be functionally modulated by ICI treatment Sanseviero et al, 2019).…”

“…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). In aggregate, those studies did not provide mechanistic bases for the identified associations.…”

Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects

“…They found that anti-CTLA-4 binding to FcRs has been linked to depletion of intratumoral Tregs, and further coincided with activation and degranulation of intratumoral NK cells. Combination therapy with anti-CTLA-4 plus IL15/IL15Rα complexes enhanced tumour control compared with either monotherapy [ 169 ]. Fc-region–modified anti-CTLA-4 mAb with high antibody-dependent cell-mediated cytotoxicity (ADCC) and cellular phagocytosis (ADCP) activity selectively depleted CTLA-4 + Foxp3 + Tregs and consequently expanded tumour antigen-specific CD8 + T cells.…”

Influence of the Tumor Microenvironment on NK Cell Function in Solid Tumors

“…Moreover, anti-CTLA-4 combined with IL-15/IL-15Rα enhances the NK cell tumor infiltration, improving the tumor growth control in xenograft murine models of solid tumors. Melanoma patients treated with anti-CTLA-4 (ipilimumab) had higher intratumoral CD56 expression(171). Consistently, several phase I and II clinical trials are ongoing to test the efficacy of different anti-PD1, anti PD-L1, and anti-CTLA-4 mAbs, alone or in combination with other Abs, in multiple forms of advanced and metastatic solid tumors (…”