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Fig. 7 | Journal for ImmunoTherapy of Cancer

Fig. 7

From: α-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by α-TGFβ antibody to promote durable rejection and immunity in squamous cell carcinomas

Fig. 7

Heterogeneous mechanisms of tumor response to α-PD-1 and α-TGFβ therapy. a Unsupervised hierarchical clustering of indicated immune cell sub-populations in tumors after treatment with control IgG, α-PD-1, α-TGFβ, or combination therapy. Tumors were classified into responders (light green), stable disease (dark green) or non-responders (red) as described in Methods (colored horizontal bar). Responding mice tend to cluster into two groups that we label Responding Cluster A and Responding Cluster B, while non-responding mice tend to cluster into a third group (Cluster C). Mice in the two responding groups had significantly better outcomes than mice in the nonresponding cluster (p = 0.02, Fisher’s Exact test). Immune profiles of tumor infiltrates in Cluster B are characterized by high T cell levels and relatively low LyC6–macrophages (TAM2s), while those in Cluster A are characterized by low levels of all immune cell subtypes except CD4+ T cells, in particular high CD4 + FoxP3–CD25– (T helper) cells. b Unsupervised hierarchical cluster analysis undertaken according to expression of a Treg transcriptomic signature in pre-treatment human melanoma samples from patients treated with α-PD-1 (see Supplementary Methods). Transcriptomic data from pre-treatment melanoma samples [12] were subjected to unsupervised hierarchical cluster analysis based on gene transcripts whose expression correlates with FoxP3 expression in CD4+ cells. Human tumors responses were classified according to Hugo et al. 2016 [12] and the original tumor IDs are presented at the base of the figure. Samples from patients exhibiting a response, in particular CR, tended to cluster together (P = 0.005, Fisher’s Exact test) and to have reduced expression of FoxP3-associated genes. c,d) Each SCC line, in order of decreasing TML, CCK168, CCK169, CCK62, CCK166, GEK1425, GEK1428, was used to induced tumors in mice, and treated with α-PD-1 or control IgG on Day 0 and Day 4 (Fig. 1b). On day 8, tumors were harvested for flow cytometric analysis of immune cells. c CD4+ T cells per total CD45+, d CD8+ cytotoxic T cells per total CD45+

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