Anti-VEGFR2-Interferon α Promotes the Infiltration of CD8+ T Cells in Colorectal Cancer by Upregulating the Expression of CCL5.

SUMMARY: Immunocytokines are a promising immunotherapeutic approach in cancer therapy. Anti-VEGFR2-interferon α (IFNα) suppressed colorectal cancer (CRC) growth and enhanced CD8 + T-cell infiltration in the tumor microenvironment, exhibiting great clinical translational potential. However, the mechanism of how the anti-VEGFR2-IFNα recruits T cells has not been elucidated. Here, we demonstrated that anti-VEGFR2-IFNα suppressed CRC metastasis and enhanced CD8 + T-cell infiltration. RNA sequencing revealed a transcriptional activation of CCL5 in metastatic CRC cells, which was correlated with T-cell infiltration. IFNα but not anti-VEGFR2 could further upregulate CCL5 in tumors. In immunocompetent mice, both IFNα and anti-VEGFR2-IFNα increased the subset of tumor-infiltrating CD8 + T cells through upregulation of CCL5. Knocking down CCL5 in tumor cells attenuated the infiltration of CD8 + T cells and dampened the antitumor efficacy of anti-VEGFR2-IFNα treatment. We, therefore, propose upregulation of CCL5 is a key to enhance infiltration of CD8 + T cells in metastatic CRC with IFNα and IFNα-based immunocytokine treatments. These findings may help the development of IFNα related immune cytokines for the treatment of less infiltrated tumors.

αVEGFR2-MICA fusion antibodies enhance immunotherapy effect and synergize with PD-1 blockade.

Antiangiogenic therapy has shown significant clinical benefits in gastric cancer (GC) and non-small cell lung cancer (NSCLC). However, their effectiveness is limited by the immunosuppressive tumor microenvironment. The MHC class I chain-related molecules A and B (MICA/B) are expressed in many human cancers, enabling elimination of cancer cells by cytotoxic lymphocytes through natural killer group 2D (NKG2D) receptor activation. To improve antiangiogenic therapy and prolong its efficacy, we generated a bi-specific fusion protein (mAb04-MICA). This was comprised of an antibody targeting VEGFR2 fused to a MICA α1-α2 ectodomain. mAb04-MICA inhibited proliferation of GC and NSCLC cells through specific binding to VEGFR2 and had superior anti-tumor efficacy in both GC and NSCLC-bearing mouse models compared with ramucirumab. Further investigation revealed that the mAb04-MICA promoted NKG2D+ NK cell activation and induced the tumor-associated macrophage (TAM) polarization from M2 type to M1 type both in vitro and in vivo. The polarization of TAMs upon NKG2D and MICA mediated activation has not yet been reported. Moreover, given the up-regulation of PD-L1 in tumors during anti-angiogenesis therapy, anti-PD-1 antibody enhanced the anti-tumoral activity of mAb04-MICA through stimulating infiltration and activation of NKs and CD8+T cells in responding tumors. Our findings demonstrate that dual targeting of angiogenesis and NKG2D, or in combination with the PD-1/PD-L1 blockade, is a promising anti-tumor therapeutic strategy. This is accomplished through maintaining or reinstating tumor immunosurveillance during treatment, which expands the repertoire of anti-angiogenesis-based cancer immunotherapies.