Although immune checkpoint blockade therapies have demonstrated clinical efficacy in cancer treatment, harnessing this strategy is largely encumbered by resistance in multiple cancer settings. Here, we show that tumor-infiltrating T cells are severely exhausted in the microsatellite stable (MSS) colorectal cancer (CRC), a representative example of PD-1 blockade–resistant tumors. In MSS CRC, we found wound healing signature to be up-regulated and that T cell exhaustion is driven by vascular endothelial growth factor-A (VEGF-A). We report that VEGF-A induces the expression of transcription factor TOX in T cells to drive exhaustion-specific transcription program in T cells. Using a combination of in vitro, ex vivo, and in vivo mouse studies, we demonstrate that combined blockade of PD-1 and VEGF-A restores the antitumor functions of T cells, resulting in better control of MSS CRC tumors.

Purpose: Immune-checkpoint inhibitors have shown therapeutic efficacy in various malignant diseases. However, antiprogrammed death (PD)-1 therapy has not shown clinical efficacy in multiple myeloma.Experimental Design: Bone marrow (BM) mononuclear cells were obtained from 77 newly diagnosed multiple myeloma patients. We examined the expression of immune-checkpoint receptors in BM CD8 þ T cells and their functional restoration by ex vivo treatment with anti-PD-1 and TGFb inhibitors.Results: We confirmed the upregulation of PD-1 and PD-L1 expression in CD8 þ T cells and myeloma cells, respectively, from the BM of multiple myeloma patients. PD-1-expressing CD8 þ T cells from the BM of multiple myeloma patients coexpressed other checkpoint inhibitory receptors and exhibited a terminally dif-ferentiated phenotype. These results were also observed in BM CD8 þ T cells specific to myeloma antigens NY-ESO-1 and HM1.24. BM CD8 þ T cells from multiple myeloma patients exhibited reduced proliferation and cytokine production upon T-cell receptor stimulation. However, anti-PD-1 did not increase the proliferation of BM CD8 þ T cells from multiple myeloma patients, indicating that T-cell exhaustion in multiple myeloma is hardly reversed by PD-1 blockade alone. Intriguingly, anti-PD-1 significantly increased the proliferation of BM CD8 þ T cells from multiple myeloma patients in the presence of inhibitors of TGFb, which was overexpressed by myeloma cells.Conclusions: Our findings indicate that combined blockade of PD-1 and TGFb may be useful for the treatment of multiple myeloma.

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Immune checkpoint inhibitor (ICI) became a standard treatment for advanced renal cell carcinoma (RCC). However, clinically valid biomarkers of therapeutic outcome are lacking. We investigated the role of interleukin-10 (IL-10) as a predictive biomarker for first-line ICI therapy in patients with advanced RCC. Baseline serum samples were prospectively collected and analyzed using a cytometric bead assay. Patients were divided into two groups according to their serum IL-10 levels using maximally selected rank statistics. A fraction (13.0%) of patients had high levels of serum IL-10 at baseline. High serum IL-10 levels (> 4.3 ng/mL) were associated with a significantly shorter progression-free (median: 5.2 months vs. not reached, P = 0.007) and overall survival (median: 13.9 months vs. not reached, P < 0.001). Multivariate Cox regression analysis confirmed the independent association between high serum IL-10 levels and poor survival outcomes. Effector cytokine production and the proliferative response of CD8 + T cells were significantly lower in patients with high serum IL-10 levels, who also had a shorter duration of response to first-line ICI therapy (4.6 months vs. not reached, P < 0.001). In conclusion, elevated serum IL-10 levels at baseline were associated with reduced clinical benefit from first-line ICI therapy in patients with advanced RCC.

<p>Supplementary Table S4</p>